Why are primary cardiac cancers in mammals so rare? It is the rhytmic beating heart!

Good news! Cancer is history (soon)!

"Primary cardiac tumors—cancers that develop in the heart—are exceptionally rare. New research in Science suggests that this low incidence may be because the heart beats: The continuous mechanical stress seems to stymie cancer growth.

In one experiment, researchers introduced potent cancer-driving mutations into mice that often develop tumors. Cancers occurred elsewhere in the body, but not in the heart. The team next created a side-by-side comparison within the same animal by observing a native heart still pumping under normal strain, and a donor heart kept alive with blood flow but without having to do the mechanical work of pumping. Tumors grew preferentially in the lower-strain heart.

Researchers saw the same effect after injecting several types of human cancer cells directly into heart tissue: In beating hearts, many remained as only small clusters, while in less-strained hearts, they grew larger.

Further analyses showed that cancer cells in beating hearts had weirdly shaped nuclei, condensed chromatin, more tightly packed DNA, and lower activity in genes tied to growth and cell division.

The team also rhythmically stretched cancer cells in the lab and concluded that strain alone could reproduce some of these antigrowth features. ... the team is already testing prototype devices designed to rhythmically compress superficial tumors, in the hopes of recreating the heart’s protective mechanism. ... it may be possible to recreate the effect of mechanical strain pharmacologically, providing new avenues for cancer treatments."

"... The rhythmic beating of the heart may play an unexpected role in protecting it from cancer. An international study ... demonstrates that the mechanical forces generated by cardiac contraction can significantly slow tumour growth in both mouse and human hearts. ..."

From the abstract (Perspective):

"Heart cancer is very rare in mammals. Moreover, the healthy adult heart does not regenerate. Human heart cells (cardiomyocytes) renew at an ~1% rate per year. The high mechanical load placed on cardiac tissue, which must overcome strong resistance to pump blood to all body organs, has been proposed to inhibit cardiomyocyte proliferation. Indeed, reducing the mechanical load on the heart promotes the expression of cell cycle markers in cardiomyocytes of patients whose hearts were unloaded by a ventricular assist device. ... report that the constant mechanical load to which cardiac tissue is subjected also inhibits the proliferation of cancer cells in the heart."

From the editor's summary and abstract:

"Editor’s summary

It is very rare for cancer to either form in or metastasize to the heart, suggesting that there is something that inhibits cancer growth in the cardiac microenvironment.

A key potential explanation is mechanical load. Ciucci et al. tested this idea by introducing cancer cells into rodent hearts and then in vitro engineering cardiac models with or without normal mechanical load.

They also compared human tissue samples from rare cardiac metastases and corresponding extracardiac tumors. The authors determined that increased mechanical load promoted Nesprin-2 signaling, which then led to changes in chromatin compaction and histone methylation, resulting in the suppression of cancer growth  ...

Structured Abstract

INTRODUCTION

The heart is rarely affected by cancer; both primary cardiac tumors and metastases are uncommon despite the high vascularization of the myocardium. The mechanisms underlying this resistance remain unclear.

RATIONALE

Mechanical load has been proposed as a major mechanism halting cardiomyocyte proliferation early after birth, thus limiting the regenerative potential of the adult mammalian heart. We hypothesized that it could similarly hamper the proliferation of cancer cells in the heart.

RESULTS

We first used an in vivo genetic model of cancer in mice, in which Cre-mediated recombination results in the overexpression of mutated K-Ras and deletion of p53, to confirm that the heart resists oncogenic events. Despite a comparable extent of recombination in liver, heart, and skeletal muscle, multiple cancers arose at different anatomical sites but never in the heart.

In addition, we set up a mouse model of heterotopic heart transplantation to mechanically unload the heart in vivo. In this model, the aorta and pulmonary artery of the transplanted heart are surgically connected with the carotid artery and external jugular vein of the recipient animal, respectively, thereby restoring perfusion in the absence of mechanical load within the left ventricle. In parallel, we used engineered heart tissues in which mechanical load can be controlled at will.

In these models, mechanical load inhibited, whereas tissue unloading promoted the proliferation of lung adenocarcinoma, colon carcinoma, and melanoma cells within the myocardium.

To investigate the mechanisms underlying these effects, we used spatial transcriptomics to analyze samples of human cancers that gave rise to both cardiac and extracardiac metastases. We found that cardiac metastases shared a common transcriptional profile, independent from the origin of the primary tumor. Among the most up-regulated genes in cardiac metastases were histone demethylases. Consistently, cardiac metastases showed reduced histone 3 lysine 9 trimethylation and reduced chromatin compaction. Similar findings were observed in our experimental models of cardiac load modulation in which chromatin accessibility and histone methylation were altered at sites controlling cancer cell proliferation, as determined by single-nuclei assay for transposase-accessible chromatin with sequencing and chromatin immunoprecipitation sequencing. Nesprin-2, a protein known to mediate mechanotransduction from the cytoplasm to the nucleus, emerged as a key molecule sensing mechanical forces operating in beating hearts and translating them into reduced cell proliferation.

Silencing of Nesprin-2 in lung cancer cells prior to their implantation in the heart in vivo restored the capacity of the cells to proliferate in the presence of physiological mechanical load, resulting in the formation of large tumors.

CONCLUSION

Collectively, these results shed light on the role of mechanical forces in protecting the heart from cancer and may pave the way to cancer therapies based on mechanical stimulation."

ScienceAdviser

Heartbeat’s Mechanical Force Found to Suppress Tumour Growth (original news release)

The heart puts pressure on cancer growth (Perspective, no public access) "Mechanical forces in the heart prevent tumor expansion in mice"

Mechanical load inhibits cancer growth in mouse and human hearts (no public access)

Designing better weapons to fight prostate cancer based on distinct tissue niches

Good news! Cancer is history (soon)!

"... A new study in the journal Immunity reveals that the prostate has its own defense force and unlocks key insights into how this army of cells, known as tissue-resident memory CD8 T cells, or Trm cells, works.

“We found that different types of T cells live in different areas, or neighborhoods, within the tissue, and where they live determines how they behave,” ..."

From the highlights and abstract:

"Highlights

• Long-lived prostate Trm cells protect against reinfection

• The prostate Trm population is heterogeneous in mice and humans

• IL-15, IL-7, and TGFβ differentially regulate prostate Trm cell subsets

• Distinct prostate cytokine and chemokine niches define Trm cell heterogeneity

Summary

The prostate is an important exocrine organ, a barrier tissue of the male reproductive system, and a common site of malignancy, yet CD8+ T cells in the prostate remain largely uncharacterized.

Here, we show that a protective, heterogeneous pool of long-lived, tissue-resident memory CD8+ T (Trm) cells forms in the prostate following acute infection in mice.

Characterization of prostate Trm cell differentiation over time, combined with functional interrogation of TGFβ, IL-7, and IL-15 signaling, revealed niche-dependent phenotypic and functional diversity arising from distinct prostate stromal and glandular epithelial niches in both mice and humans. 

For instance, the Trm-promoting cytokines IL-15 and TGFβ were highest in the prostate epithelium, where CD8+ T cells were most persistent, cytotoxic, and enriched for the Trm molecular program.

In sum, we provide a spatial framework for prostate Trm cell differentiation, charting the discrete tissue regions that influence T cell fate through dynamic regulation of localized signals."

Designing better weapons to fight prostate cancer - Allen Institute "New study unlocks key insights that could help develop next-generation immunotherapies"

Distinct tissue niches contribute to prostate tissue-resident memory CD8+ T cell differentiation and heterogeneity (open access)

Graphical abstract

Scientists confirm precursor to commonest form of oesophageal cancer – offering opportunities to catch the disease early

Good news! Cancer is history (soon)!

"The findings, ... could help improve screening for and early detection of oesophageal cancer, the sixth most deadly cancer, helping improve outcomes for the disease.

Cancer of the oesophagus, including its most common form oesophageal adenocarcinoma (OAC) ...

To answer the question of whether Barrett’s oesophagus is a pre-requisite for OAC, researchers ... analysed epidemiological and clinical data from 3,100 OAC patients undergoing surgery to remove their tumour or diseased tissue. Patients were recruited from 25 centres across the UK.

The team also analysed whole genome sequencing data from 710 patients, which allows them to look at all of an individual’s DNA, and whole exome sequencing from multiple samples taken from 87 patients, allowing them to understand how their tumours evolved and how different parts of the same cancer may differ genetically.

The researchers hypothesised that if OAC can arise through different routes – not always involving Barrett’s oesophagus – then genomic data and associated risk factors would differ between these two groups. Conversely, extensive overlap would strongly suggest that Barrett’s oesophagus plays a central role in OAC progression.

Just over a third of participants (35%) had a diagnosis of Barrett’s oesophagus. However, the DNA, mutations, genomic patterns, and cellular ‘identity’ inside the cancers were essentially indistinguishable, regardless of whether doctors could identify Barrett’s oesophagus during endoscopy or in pathology samples.

The only major difference between cancers with or without visible Barrett’s oesophagus was the tumour stage – those patients without signs of Barrett’s oesophagus tended to have more advanced cancers.

However, the team found biomarkers for Barrett’s oesophagus, such as the proteins TFF3 and REG4 present in the oesophagus cells at all disease stages including before the cancer has developed. This suggests that the growing tumour can destroy the original Barrett’s tissue, but importantly that proteins such as TFF3 and REG4 could be used to find individuals at future risk of oesophageal cancer. ..."

From the abstract:

"Cancer generally takes years to evolve, and early diagnosis can prevent life-threatening cancer. Establishing a link between precancerous states and cancer is essential for effective screening and prevention.

Esophageal adenocarcinoma (EAC) is an increasingly prevalent, poor-outcome cancer, and its presumed precursor, Barrett’s esophagus (BE), characterized by intestinal metaplasia, is evident in only about half of cases.

Here to test whether BE is a prerequisite to EAC, we integrated epidemiological and clinical characteristics in a prospective cohort of 3,100 patients with EAC for any evidence of BE (BE-positive and BE-negative) and compared genomic features using a subset of 710 patients with whole-genome sequencing and 87 patients (380 samples) with multiregional whole-exome sequencing. Demographic and genomic features typically associated with BE were observed across BE-positive and BE-negative EAC cases.

Notably, molecular features consistent with early BE evolution were detected in both phenotypes.

Advanced tumor stage was the only variable that corresponded with increased likelihood of BE-negative EAC, including in some patients with a previous BE diagnosis.

Phylogenetic analyses revealed shared evolutionary trajectories, and spatial transcriptomic and proteomic analyses demonstrated intestinal metaplasia-associated lineage markers in both groups.

These findings suggest a single pathway to EAC, with implications for early diagnosis and prevention strategies."

Scientists confirm precursor to commonest form of oesophageal cancer – offering opportunities to catch the disease early | University of Cambridge "Scientists have found the strongest evidence to date that a condition known as Barrett’s oesophagus is the starting point for all cases of oesophageal adenocarcinoma – the most common type of oesophageal cancer in the developed world – even when telltale signs of this pre-cancerous stage are no longer visible."

Integrated epidemiological and molecular data inform the relationship between precancer and cancer states of esophageal adenocarcinoma (open access)

Fig. 1: The study design to establish whether there is a BE-independent pathway to EAC.

Leukemia cells use a sugar-coated protein to hide from the immune system

Good news! Cancer is history (soon)!

"Highlights

• Study reveals previously unrecognized way for cancer to evade the immune system. 
• Other cancers could also be using sugar-coated proteins to shield themselves from immune attack.
• Findings suggest CD43 is a potential target for new cancer immunotherapies.

...

Now, researchers have identified a key part of the cancer’s disguise: a protein called CD43 on the surface of leukemia cells that is coated so heavily in sugar molecules that it forms a physical barrier, shielding the cells from immune attack. ..."

From the abstract of the Perspective:

"Immune cells continually detect, engulf, and destroy invasive microbes and cancer cells. This process, called phagocytosis, is carried out by macrophages that must distinguish between proengulfment signals and inhibitory (“don’t-eat-me”) warnings.

Cluster of differentiation 47 (CD47), a cell-surface receptor, is the archetypal don’t-eat-me signal.

Many cancers upregulate CD47 expression to escape phagocytosis, and CD47 blockade promotes phagocytosis of cancer cells in mice.

However, CD47 blockers have not shown clinical benefits in patients with acute myeloid leukemia (AML), an aggressive cancer of blood immune cells. This discrepancy has raised the possibility that the molecular programs that inhibit phagocytosis differ between mice and humans. On page 174 of this issue, Chung et al. report that the mechanisms that control macrophage function in human and mouse cells are indeed different. They also identify cluster of differentiation 43 (CD43) as a potential target for human AML treatment."

From the editor's summary and abstract:

"Editor’s summary

Phagocytosis is a process used by immune cells called macrophages to destroy pathogens and cellular debris.

Tumor cells can evade killing by macrophage-mediated phagocytosis by deploying decoy signals to the immune system.

Chung et al. performed a CRISPR screen of human acute myeloid leukemia (AML) cells to identify phagocytic regulators ... 

The surface protein CD43 was found to be coated in a high-density shield of sialic acid residues that effectively functioned as a “don’t eat me” signal to limit immune clearance.

Inactivation of CD43 function restored the ability of macrophages to phagocytize AML. Strategies that disable sialylated glycans may therefore have potential to enhance phagocytosis and targeting of AML. ...

Structured Abstract

INTRODUCTION

Macrophages in the tumor microenvironment exert antitumorigenic effects through phagocytosis and/or direct tumoricidal activity.

Phagocytosis of tumor cells occurs through both antibody-dependent cellular phagocytosis (ADCP) and antibody-independent cellular phagocytosis (AICP) mechanisms. Despite the strong evidence that macrophages can mediate tumor control in acute myeloid leukemia (AML) and other diseases, therapeutic agents that enhance macrophage phagocytosis, including anti-CD47 neutralizing antibodies, have not led to improved clinical outcomes. Thus, a more comprehensive understanding of the tumor-intrinsic factors that suppress human macrophage phagocytosis is needed.

RATIONALE

To systematically identify the key pathways that regulate phagocytosis by human macrophages, we performed genome-scale knockout CRISPR screens in human AML cell lines cocultured with human monocyte-derived macrophages.

RESULTS

We performed in vitro genome-wide loss-of-function CRISPR screens to identify the major pathways that regulate ADCP and AICP by human macrophages. Unexpectedly, we found that the classic “don’t eat me” signal CD47 has minimal impact on human macrophage phagocytosis.

By contrast, CD47 strongly suppressed mouse macrophage phagocytosis. Additionally, we identified the major histocompatibility class I complex (MHC class I) as the most potent negative regulator of ADCP.

By integrating results from the AICP and ADCP screens, we discovered that the O-linked glycosylation and sialylation pathways negatively regulate both AICP and ADCP.

CD43, a heavily sialylated cell surface glycoprotein, was the major mediator of the inhibitory effects of the O-linked glycosylation and sialylation pathways.

The inhibitory activity of CD43 was dependent on its sialic acid residues and the length of its ectodomain but independent of the canonical sialic acid–binding receptors SIGLEC-1, SIGLEC-7, and SIGLEC-9. CD43 expression reduced the avidity of interactions between immune effector cells and leukemia cells, consistent with a model where CD43 forms a steric or electrostatic glycocalyx barrier that reduces interactions with the leukemia cell surface.

We found that CD43 is overexpressed in AML patient samples, and inhibition of CD43 with antibodies enhances phagocytosis of AML cell lines and patient-derived samples.

Finally, we found that CD43 not only restrains human macrophage phagocytosis but also human natural killer (NK) and human T cell cytotoxicity.

CONCLUSION

The cell surface glycoprotein CD43 is a potent inhibitor of innate and adaptive antileukemic immunity. The inhibitory activity of CD43 on immune cells is dependent on posttranslational sialic acid modifications that are added through the O-linked glycosylation and sialylation pathways. Thus, sialylated CD43 is a potential therapeutic target for the treatment of AML."

Leukemia cells use a sugar-coated protein to hide from the immune system | Broad Institute "Targeting this protein, called CD43, could offer a new path to treatment for leukemia and other cancers."

The sialic shield of leukemia cells (Perspective, no public access)

Sialylated CD43 forms a glyco-immune barrier that restrains antileukemic immunity (no public access)

Genome-scale phagocytosis screens identify sialylated CD43 as a potent inhibitor of antileukemic immunity.

Inexpensive detecting of multiple cancers and other diseases from a single blood sample by analyzing circulating DNA fragments

Good news! Will we soon have much better and cheaper health checkups?

"UCLA scientists have developed a simple and cost-effective blood test that, in early studies, shows promise in detecting multiple cancers, various liver conditions and organ abnormalities simultaneously by analyzing DNA fragments circulating in the bloodstream. The test, described in the journal Proceedings of the National Academy of Sciences, could offer a powerful and more affordable approach to early disease detection and comprehensive health monitoring. ..."

"Key takeaways

• In early studies, the blood test, developed by UCLA scientists, shows promise in detecting multiple cancers.
• The new method, called MethylScan, works by analyzing cell-free DNA, tiny fragments of genetic material released into the blood when cells die.
• In tests, MethylScan detected about 63% of cancers across all stages and roughly 55% of early-stage cancers. 

..."

From the significance and abstract:

"Significance

Cell-free DNA (cfDNA) in blood carries molecular signals from multiple organs, offering a powerful, noninvasive way to detect disease and monitor health. Current cfDNA methylation tests are costly and usually focus on a single condition.

We developed MethylScan, a low-cost assay that sequences cfDNA methylome from blood. In over 1,000 individuals, MethylScan shows robust performance across a range of clinical applications, including multicancer detection in the general population, liver cancer surveillance in high-risk individuals, liver disease classification, organ injury detection, and ancestry prediction, all from one blood sample. This versatile approach enables affordable, wide-ranging cfDNA tests that can identify various health conditions simultaneously, with the potential to transform early disease detection and health monitoring across diverse clinical settings.

Abstract

Plasma cell-free DNA (cfDNA), originating from multiple organs, holds significant potential for noninvasive diagnostics and prognostics. Current cfDNA methylation assays primarily focus on single clinical indications by targeting specific genomic loci. In contrast, comprehensive profiling of cfDNA methylome can enable simultaneous detection of multiple diseases by capturing organ-specific methylation signatures, thereby offering a holistic view of health, when disease etiology is unclear or when conventional biochemical diagnostics are unavailable. However, deep sequencing required for sensitive detection of methylation abnormalities remains prohibitively expensive, limiting widespread clinical use. To overcome this barrier, we developed MethylScan, a highly cost-effective approach for cfDNA methylome sequencing. We demonstrated its broad clinical utility in a cohort of 1,061 individuals across diverse applications, including multicancer detection in general population, liver cancer surveillance in high-risk individuals, liver disease classification, identification of organ abnormalities, and race prediction from cfDNA.

In multicancer detection (liver, lung, ovarian, and stomach cancers), MethylScan achieved an area under the receiver operating characteristic curve (AUROC) of 0.938 (95% CI: 0.920 to 0.954), with a sensitivity of 63.3% (95% CI: 58.9 to 67.9%) at 98.0% specificity for all cancer stages.

For early-stage cancers, the AUROC was 0.916 (95% CI: 0.890 to 0.940), with 55.3% sensitivity (95% CI: 49.1 to 62.1%) at the same specificity.

In liver cancer surveillance, MethylScan achieved an AUROC of 0.927 (95% CI: 0.889 to 0.959), with 79.6% sensitivity (95% CI: 70.6 to 87.8%) at 90.4% specificity.

The assay also demonstrated strong performance in additional diagnostic tasks, supporting its potential as a versatile platform for comprehensive cfDNA-based health monitoring."

Detecting multiple cancers and other diseases from a single blood sample

UCLA researchers develop low-cost blood test to detect multiple cancers and other diseases from a single sample (original news release)

Toward the simultaneous detection of multiple diseases with a highly cost-effective cell-free DNA methylome test (open access)

Fig. 1 Illustration of the principle of the MethylScan assay and the criteria of choosing target regions of the MethylScan panel. Shown are four genomic regions, of which the middle two regions have consistent unmethylated MSRE cutting sites in the background cfDNA and are therefore included in the MethylScan panel.

In Step 1, upon MSRE digestion, the background cfDNA in the two panel regions are removed.

In Step 2, the target panel specifically captures cfDNA from the panel regions, thereby enriching tumor cfDNA in the final sequencing pool.

Fig. 4 Study design. (A) overview of plasma samples. (B–F) the usage of plasma samples in five studies. (G) the usage of tissue samples.

Dendritic cells power down inside tumors—re-energizing them could help treat cancer

Good news! Cancer is history (soon)!

"Dendritic cells ... By using their long projections to display fragments of protein, they summon other immune cells to attack invaders and destroy diseased cells. But when dendritic cells find themselves inside a tumor, they tend to run out of steam. According to new research, these cells stop working because their mitochondria ... become degraded.

When scientists examined mice with melanoma, they found that some dendritic cells within the animals’ tumors had perfectly healthy mitochondria, while others were debilitated.

As the tumors grew, the number of cells with active mitochondria dwindled. Although it’s unclear exactly why these organelles go on the fritz, the team did determine that a protein called OPA1 appears to be essential to their functioning. Dendritic cells that possessed this protein were much better at rallying other immune cells, while those engineered to lack it were far less effective—leading to more tumor growth.

When the researchers injected the rodents’ dendritic cells with lots of additional mitochondria, the animals were able to mount a strong antitumor response and fared better when treated with a type of immunotherapy. ..."

From the Perspective abstract:

"Dendritic cells are innate immune cells that regulate the quality, magnitude, and duration of antitumor responses. Conventional type 1 dendritic cells (cDC1s) are crucial in this capacity but are paradoxically rare and functionally impaired in most solid tumors. This is a major barrier to effective immunotherapy. The molecular underpinnings of cDC1 dysfunction within the tumor microenvironment are poorly understood. On page 55 of this issue, You et al. (1) report that mitochondrial fitness is important for cDC1 function. They also demonstrate the therapeutic rescue of cDC1 function within the tumor microenvironment in mice, which provides a framework for metabolically reprogramming dendritic cells to restore antitumor immunity."

From the editor's summary and abstract:

"Editor’s summary

Type 1 conventional dendritic cells (cDC1s) promote CD8+ T cell–mediated antitumor responses. However, cDC1s can become dysfunctional in the tumor microenvironment, and the mechanisms governing cDC1 function versus dysfunction in cancer remain unclear. You et al. report that mitochondrial metabolic states and signaling direct cDC1 function in antitumor immunity (see the Perspective by Molina and Haldar). Loss of the mitochondrial protein OPA1 disrupted nuclear respiratory factor 1 (NRF1) activity and electron transport chain integrity, leading to defects in mitochondrial bioenergetics and redox balance in cDC1s, accompanied by reduced tumor control. OPA1-NRF1 signaling progressively declined during tumor progression, and tumor-bearing mice receiving cDC1s with high mitochondrial fitness had improved antitumor responses, especially in combination with immunotherapy. Therefore, “metabolic engineering” of cDC1s may provide a mechanism for cancer immunotherapy. —Priscilla N. Kelly

Structured Abstract

INTRODUCTION

Conventional type 1 dendritic cells (cDC1s) are essential for cytotoxic CD8+ T cell responses in cancer immunity and immunotherapy. Although previous studies have suggested that mitochondrial oxidative phosphorylation (OXPHOS) is dispensable for DC maturation in vitro and represents a hallmark of tolerance in human monocyte–derived DCs, whether and how mitochondrial metabolism regulates cDC1-CD8+ T cell interactions in antitumor immunity remain largely unknown. In this study, we reveal that intratumoral cDC1s have discrete mitochondrial states and that mitochondrial fusion protein OPA1 dictates cDC1 antitumor immunity by facilitating mitochondrial energy and redox metabolism.

RATIONALE

Despite the success of immunotherapy in cancer treatment, therapeutic resistance or relapse occurs in a large subset of patients. cDC1s determine antitumor effects and therapeutic benefits upon immune checkpoint blockade (ICB) by orchestrating CD8+ T cell activation and function. However, cDC1s often experience metabolic stress and exhibit decreased functional fitness within the tumor microenvironment. ...

RESULTS

We established, from both mouse and human tumors, that cDC1s exhibit discrete mitochondrial states.

One subpopulation, referred to as [TMRM/MG]hi cells, contained polarized mitochondria, as demonstrated by the ratio of mitochondrial membrane potential [measured with tetramethylrhodamine methyl ester perchlorate (TMRM)] compared with mitochondrial mass [measured with MitoTracker Green (MG)]; whereas the 

other subpopulation, [TMRM/MG]lo cells, had depolarized mitochondria. Intratumoral cDC1s with polarized mitochondria more effectively primed CD8+ T cell responses than those with depolarized mitochondria.

Using unbiased profiling approaches and experimental validations, we uncovered that OPA1 orchestrates the mitochondrial states and morphology in intratumoral cDC1s.

Notably, OPA1 deletion in cDC1s led to increased tumor growth and impaired antitumor CD8+ T cell responses, corresponding to defective antigen presentation by cDC1s. Mechanistically, we established that OPA1 supports nuclear respiratory factor 1 (NRF1) activity and expression to sustain mitochondrial OXPHOS in cDC1s. OPA1-NRF1 axis–mediated OXPHOS inhibited autophagy and lysosome–dependent degradation of major histocompatibility complex I (MHC-I) and antigen. In addition, OPA1-mediated electron transport chain (ETC) flow contributed to cDC1 immunogenicity by facilitating NADH-to-NAD+ conversion (i.e., conversion from the reduced to the oxidized form of nicotinamide adenine dinucleotide). These OPA1-dependent effects were antagonized by mitochondrial fission protein DRP1.

During tumor progression, intratumoral cDC1s experienced a progressive mitochondrial dysfunction, as revealed by reduction of the [TMRM/MG]hi subpopulation as well as decreased mitochondrial volume and OPA1-NRF1 signaling.

Intratumoral administration of tumor antigen–pulsed cDC1s with polarized mitochondria into tumor-bearing mice resulted in superior tumor control compared with cDC1s with depolarized mitochondria, particularly when combined with ICB therapies. Indeed, a substantial proportion of mice receiving cotreatment of tumor antigen–pulsed cDC1s with polarized mitochondria plus ICB completely rejected tumors and developed durable immune memory responses upon tumor rechallenge.

CONCLUSION

We uncovered discrete mitochondrial states and the underlying mitochondrial metabolic signaling programs in cDC1s that support their functional fitness in antitumor immunity and the establishment of durable ICB responses. These discoveries provide opportunities to reinvigorate cDC1s for improved cancer immunotherapy."

ScienceAdviser

Mitochondria power immunity against cancer (Perspective, no public access)

Mitochondrial metabolism and signaling direct dendritic cell function in antitumor immunity (no public access)

Mitochondrial metabolism and signaling orchestrate cDC1 antitumor responses.

Notes on Hyperplasia Functions as a Link Between Obesity and Cancer

Good to know! Cancer is history (soon)! I only became aware of this paper, because one of authors is Allain Yuille, a well known ML & AI researcher, who I am following via Google Scholar.

Another good reason to lose weight when overweight!

From the abstract:

"Obesity is a well-established risk factor for several cancers, yet the underlying mechanisms remain incompletely understood. We hypothesized that as body size increases with obesity, organ size increases to meet metabolic demands, which in turn raises the number of cells at risk of malignant transformation.

Measurement of the liver, pancreas, and kidney volumes in 747 adults across a wide BMI range (17.8 to 70.9 kg/m²) showed a strong positive correlation between BMI and organ size: a 5-unit increase in BMI was significantly associated with volume increases of 12% in the liver, 9% in both kidneys combined, and 7% in the pancreas.

To determine the cellular basis of organ enlargement, kidney cell numbers were quantified using both autopsy samples (34,337 proximal tubular epithelial cells) and biopsy data from 25 individuals. The total number of cells increased substantially, indicating that approximately 61% of kidney enlargement was due to hyperplasia, with the remaining 39% increase attributable to hypertrophy. Moreover, organ volume ratios, relative to volume for normal-weight adults, strongly correlated with cancer risk across the three organs, indicating that a doubling in organ volume corresponded approximately to a doubling in cancer risk. These findings suggest a mechanism linking obesity to cancer: as body size and metabolic demands increase, organs expand primarily through hyperplasia that increases the number of cells susceptible to malignant transformation, complementing known pathways involving inflammation, hormones, and metabolic dysregulation."

Hyperplasia Functions as a Link Between Obesity and Cancer | Cancer Research | American Association for Cancer Research (no public access)

Greater precision for in vivo cancer-fighting CAR T cells

Good news! Cancer is history (soon)!

"Greater precision for in vivo CAR T

Researchers have invented a two-vector system that uses CRISPR–Cas9 gene editing to create in vivo cancer-fighting CAR T cells without accidentally targeting other cells. Leukaemia and multiple myeloma were eliminated in the mice treated with these precision in vivo CAR T cells, while more than half of mice with sarcoma went into remission. Biotech company Azalea Therapeutics is testing the approach in monkeys and hopes to trial the treatment in people by the end of next year."

From the abstract:

"Engineered T cells, reprogrammed to express chimeric antigen receptors (CAR) or T cell receptors (TCR), have transformed cancer treatment and are being explored as therapeutics for autoimmune and infectious diseases. Enhancing T cell function through genome editing, either by disrupting endogenous genes or precisely inserting DNA payloads, has shown considerable promise. However, the ex vivo manufacturing process is lengthy and costly, limiting accessibility of these therapies. In vivo generation of CAR T cells could overcome these barriers, but current methods rely either on transient expression with limited durability, or on random integration of DNA payloads that lack specificity.

Here we demonstrate that stable and cell-specific transgene expression can be achieved through in vivo site-specific integration of large DNA payloads. We developed a two-vector system to deliver CRISPR–Cas9 ribonucleoproteins and a DNA donor template, using enveloped delivery vehicles and adeno-associated viruses, respectively. We optimized both vectors for T cell-specific delivery and gene-targeting efficiency.

By integrating a CAR transgene into a T cell-specific locus, we generate therapeutic levels of CAR T cells in vivo in humanized mouse models of B cell aplasia, and haematological and solid malignancies. These findings offer a pathway to more efficient, precise and widely accessible T cell therapies."

Nature briefing cancer

CRISPR makes enhanced cancer-fighting immune cells inside mice "Gene-editing technique promises a potentially safer way to create CAR T cells with a simple injection."

A gene-editing method generates immunotherapeutic CAR T cells in the body "Laboratory-engineered immune cells called CAR T cells provide effective treatment for some cancers. Progress is being made towards creating these cells in vivo." (no public access)

In vivo site-specific engineering to reprogram T cells (open access)

Fig. 1: Co-delivery of Cas9-EDV and HDRT-AAV generates TRAC-CAR T cells in vitro and in vivo.

Previous efforts to create in vivo CAR T cells have involved viral vectors (that sometimes accidentally edit ‘bystander’ cells using retroviral transduction) or lipid nanoparticles (which deliver mRNA to T cells, creating transient expression of the CAR protein). To specifically target and permanently edit T cells, the team used two vectors: a CRISPR-Cas9 gene-editing system inside ‘enveloped delivery vehicles’, and viruses that transported the DNA coding for the CAR protein.

Chart of the day

Researchers have found that intravenous administration of a nonpathogenic virus, oncolytic alphavirus M1 (OVM), suppresses the growth of glioblastoma, a lethal brain cancer, and also reverses the cancer’s suppression of the immune system. OVM triggers an immune response to cell death (ICD), restoration of the immune system, tumour microenvironment (TME) reprogramming and proliferation of immune cells that specifically target the tumour. (Source)

 

What Happens When an incarcerated criminal Gets Cancer in Prison?

Bad news! One more good reason to stay out of prison!

What this PJP may not have investigated is how much prisoners were themselves negligent or ignorant to diagnose and undergo treatment? 

"People who are imprisoned are more likely to die from cancer than the general population in the United States. Chronic stress and unhealthy food contribute to poor cancer outcomes, as do delays in diagnosis, patchy treatment and lack of coordination with outside healthcare systems. Contributors to the Prison Journalism Project (PJP) reported symptoms being ignored or downplayed, follow up appointments being missed because of administrative failures or resourcing issues and being strip-searched and chained when seeing doctors, receiving treatments or travelling for healthcare. PJP contributors described recovering from cancer in prison as a unique kind of hell." (Nature Briefing Cancer)

What Happens When You Get Cancer in Prison? — Prison Journalism Project "PJP contributors on what it’s like to suffer from the leading killer behind bars."

Unusual tumor cells may be overlooked factors in advanced breast cancer

Good news! Cancer is history (soon)!

"An enigmatic type of circulating tumor cell called a dual-positive (DP) cell is associated with shorter survival time in patients with advanced breast cancer, according to a study ...

The findings highlight the potential importance of these under-studied cells in breast cancer progression.

Circulating tumors cells are breakaway tumor cells that can seed secondary tumors (metastases) and are commonly detected in the blood of patients with cancer.

Dual-positive cells are circulating cells that bear both tumor-cell and immune-cell markers and are thought to be hybrid cells resulting from rare fusions of tumor cells with immune cells. Recent studies have linked DP cells’ presence in patients’ blood to worse outcomes in melanoma and pancreatic cancer.  ...

researchers linked DP cells to shorter survival times in patients with advanced breast cancer, especially the aggressive “triple-negative” breast cancer subtype. The team also showed with animal models that DP cells can seed breast cancer metastases. ..."

From the editor's summary and abstract:

"Editor’s summary

Circulating tumor cells (CTCs) are tumor cells that are present in the blood of patients with cancer that rarely express both epithelial and leukocyte markers, termed dual-positive cells (DPcells). Here, Reduzzi et al. evaluate the prognostic ability of these DPcells in patients with breast cancer (BC) to predict prognosis and create a preclinical mouse model of BC to understand their metastatic ability. They show association of DPcells with worse overall survival, and genomic alterations confer increased metastatic ability in mouse models. This suggests the potential of DPcells in guiding patient treatment that warrants further study.  ...

Abstract

Metastasis is the leading cause of death in patients with breast cancer (BC), but the mechanisms underlying metastasis formation are still poorly understood. Circulating tumor cells (CTCs) are considered the main seed of metastasis with demonstrated prognostic impact in patients with BC. They are conventionally identified as cells positive for epithelial markers and lacking leukocyte markers. Nonetheless, circulating cells expressing both markers [dual-positive cells (DPcells)] have been reported but poorly investigated.

Here, we evaluated, in a cohort of 340 patients with advanced BC, the prognostic impact of DPcells, showing their association with worse survival, particularly in patients with less than five CTCs. Their prognostic value varied among BC subtypes, with greater relevance observed in triple-negative and HER2-positive BC. Moreover, by performing single-cell genomic profiling of DPcells isolated from patients, we detected genomic aberrations in 28 and 93% of analyzed DPcells and CTCs, respectively.

In vivo, DPcells were detected only in the blood of immunocompetent but not immunodeficient mice and no differences in the lung metastatic colonization ability of DPcells versus control cancer cells were observed. Our findings highlight the importance of studying this overlooked subpopulation of CTCs as a prognostic biomarker in BC, which might be particularly important in specific BC subtypes. Moreover, our results support the malignancy and metastasis-forming capability of DPcells and underline the need for future studies better defining the origin of these cells."

Unusual tumor cells may be overlooked factors in advanced breast cancer | Cornell Chronicle

Dual-positive CTCs in patients with advanced breast cancer show metastatic potential and prognostic value (no public access)

Tumors Protect Themselves from Immune Attack by Talking to the Brain

Amazing stuff! Cancer is history (soon)!

"In many tumors, nerves from our peripheral nervous system establish themselves in the cancerous tissue. The new study found that tumors can hijack these nerves to send signals to the brain. This, in turn, triggers activity that blocks immune cells from infiltrating the cancer, which enables cancer growth. ...

The team then sought to understand why this happens. Using animal models of lung adenocarcinoma, they experimented with inhibiting and activating various subpopulations of neurons to see how this impacted cancer growth. They also used single cell sequencing to identify the types of neurons innervating tumors in the lung, as well as imaging techniques to visualize how nerve and cancer cells interacted with one another. Meanwhile, collaborators at the University of Pennsylvania studied the surrounding immune cells and their signaling in the cancer microenvironment. ..."

From the abstract:

"Body–brain communication has emerged as a key regulator of tissue homeostasis. Solid tumours are innervated by different branches of the peripheral nervous system and increased tumour innervation is associated with poor cancer outcomes. However, it remains unclear how the brain senses and responds to tumours in peripheral organs, and how tumour–brain communication influences cancer immunity.

Here we identify a tumour–brain axis that promotes oncogenesis by establishing an immune-suppressive tumour microenvironment.

Combining genetically engineered mouse models with neural tracing, tissue imaging and single-cell transcriptomics, we demonstrate that lung adenocarcinoma induces innervation and functional engagement of vagal sensory neurons, a major interoceptive system connecting visceral organs to the brain.

Mechanistically, Npy2r-expressing vagal sensory nerves transmit signals from lung tumours to brainstem nuclei, driving elevated sympathetic efferent activity in the tumour microenvironment. This, in turn, suppresses anti-tumour immunity via β2 adrenergic signalling in alveolar macrophages.

Disruption of this sensory-to-sympathetic pathway through genetic, pharmacological or chemogenetic approaches significantly inhibited lung tumour growth by enhancing immune responses against cancer.

Collectively, these results reveal a bidirectional tumour–brain communication involving vagal sensory input and sympathetic output that cooperatively regulate anti-cancer immunity; targeting this tumour–brain circuit may provide new treatments for visceral organ cancers."

Tumors Protect Themselves from Immune Attack by Talking to the Brain | Yale School of Medicine

Tumour–brain crosstalk restrains cancer immunity via a sensory–sympathetic axis (open access)

Fig. 1: LUAD is innervated by VSNs. [vagal sensory neuron]

Cancer protein molecule shields against Alzheimer’s

Amazing stuff!

"Scientists have found a protein made by cancer cells that protects the brain from Alzheimer’s disease in mice — potentially solving a decades-old puzzle about why cancer and Alzheimer’s disease are rarely found in the same person.

When mouse models of Alzheimer’s disease were given a transplant of lung, prostate or colon cancer, they did not develop the plaques characteristic of the brain condition. ... After more than six years of searching, they identified a cancer protein called cystatin C that could infiltrate the brain and flag brain plaques for destruction by the immune system. The breakdown of plaque improved cognitive performance in mice and, if replicated in humans, could form the basis of a new therapy."

From the highlights and abstract:

"Highlights

• Fight Alzheimer’s disease with peripheral cancers via Cyst-C secretion

• Tumor-derived Cyst-C attenuates amyloid pathology of Alzheimer’s disease

• Human Cyst-C binds amyloid oligomers and activates TREM2

• Tumor-derived Cyst-C degrades pre-existing amyloid plaques via TREM2

Summary

Alzheimer’s disease (AD) and cancer are among the most devastating diseases worldwide. Epidemiological data indicate that the incidence of AD significantly decreases in patients with a history of cancer. However, whether and how peripheral cancer may affect AD progression is yet to be studied.

Here, we find that peripheral cancer inhibits amyloid pathology and rescues cognition via secretion of cystatin-c (Cyst-C), which binds amyloid oligomers and activates triggering receptor expressed on myeloid cells 2 (TREM2) in microglia, enabling microglia to degrade the pre-existing amyloid plaques in AD mice. These effects of Cyst-C are abolished by a cell-type-specific deletion (Cx3cr1TREM2−/−) or mutation of TREM2 (TREM2R47H) or Cyst-C (Cyst-CL68Q) in microglia.

Together, these findings provide significant conceptual advances into cancer neuroscience and establish therapeutic avenues that are distinct from the present amyloid-lowering strategies, aiming at degrading the existing amyloid plaques for precision-targeted AD therapy."

Nature Briefing: Cancer

Cancer might protect against Alzheimer’s — this protein helps explain why (open access) "A molecule produced by cancer cells can shield the brain from Alzheimer’s disease in mice."

Peripheral cancer attenuates amyloid pathology in Alzheimer’s disease via cystatin-c activation of TREM2 (open access)

Graphical abstract

Moderna, Merck report cancer treatment discovery for several different cancers with Maria Bartiromo

Good news! Cancer is history (soon)! No safety risks, no side effects!

A portable ultrasound sensor may enable earlier detection of breast cancer

Amazing stuff!

Notice MIT too uses the horrible ideological term "people" for women!!!

"For people [women] who are at high risk of developing breast cancer, frequent screenings with ultrasound can help detect tumors early. MIT researchers have now developed a miniaturized ultrasound system that could make it easier for breast ultrasounds to be performed more often, either at home or at a doctor’s office.

The new system consists of a small ultrasound probe attached to an acquisition and processing module that is a little larger than a smartphone. This system can be used on the go when connected to a laptop computer to reconstruct and view wide-angle 3D images in real-time. ..."

From the abstract:

"Effective resource-constrained volumetric ultrasound imaging requires compact, low-power systems capable of wide-angle real-time 3D imaging to accommodate small changes in placement by the operator. However, obtaining such images requires an excessive O(N2) channel count, bulky electronics, and high power consumption.

We introduce an end-to-end system architecture to enable high-resolution, real-time 3D ultrasound imaging in a portable form factor. We present: a convolutional optimally distributed array (CODA) geometry that drastically reduces the number of elements (from 1024 to 128), a novel chirped data acquisition (cDAQ) architecture that enhances imaging depth while operating with a 25.3 dB lower transmit amplitude than a pulsed system, and an associated new signal processing methodology.

We experimentally demonstrate our system's ability to perform deep (> 11 cm), high axial resolution (< 600 µm), and wide-angle (57°) imaging, while simultaneously reducing power consumption (29.6x reduction) and drive voltage (18 V).

We validated our system in vitro and further performed in vivo human trials, demonstrating the ability to detect both tumors and cysts in breast tissue. This new architectural approach will unlock a new class of medical devices with enhanced diagnostic and long-term monitoring capabilities and open up future wearable designs of real-time 3D ultrasound systems."

A portable ultrasound sensor may enable earlier detection of breast cancer | MIT News | Massachusetts Institute of Technology "The new system could be used at home or in doctors’ offices to scan people who are at high risk for breast cancer."

Real-Time 3D Ultrasound Imaging with an Ultra-Sparse, Low Power Architecture (open access)

Fig. 1 Real-time 3D ultrasound imaging system architecture.

AI-supported mammography screening results significantly beat human screeners

Good news!

"Researchers have published the full results of the largest randomized trial of AI cancer screening to date, comparing mammograms read by one radiologist assisted by AI with the standard two-radiologist review.

The AI-supported process cut the radiologists’ workload by 44 percent and detected 29 percent more cancers, without additional false positives. Women who received a negative result during their AI-assisted mammogram ended up having 12 percent fewer cancer diagnoses before their next scheduled screening than those in the control group, suggesting that the AI screen missed fewer aggressive cancers."

"

• First full results of a randomised trial investigating the use of AI in a national breast cancer screening programme finds AI-supported mammography screening is more effective across many measures than standard mammography. 
• AI-supported breast cancer screening identified more women with clinically relevant cancers during the screening without a higher rate of false positives. 
• Additionally, women who underwent AI-supported screening were less likely to be diagnosed with more aggressive and advanced breast cancer in the two years following.
• Authors say these findings could justify implementing AI in mammography screening programmes, particularly in the context of health professional workforce shortages.

..."

From the abstract:

"Summary

Background

Evidence indicates that artificial intelligence (AI) can improve mammography screening by increasing cancer detection and reducing screen reading workload, but its effect on interval cancers (primary breast cancers diagnosed between two screening rounds or within 2 years after the last scheduled screening that were not detected at screening) is unknown. We aimed to compare the interval cancer rate in AI-supported mammography screening with standard double reading without AI.

Methods

In this Swedish randomised, controlled, non-inferiority, single-blinded, population-based screening accuracy trial, participants were allocated in a 1:1 ratio to either AI-supported mammography screening (the intervention group) or standard double reading without AI (the control group).

AI was used to triage examinations to single or double reading by radiologists and for detection support. This is a protocol-defined analysis of the primary outcome, interval cancer rate, with a 20% non-inferiority margin. Secondary outcomes reported in this analysis are interval cancer characteristics, sensitivity, specificity, and sensitivity by age, breast density, and cancer type (in-situ and invasive).  ...

Findings

Between April 12, 2021, and Dec 7, 2022, 105 934 women were randomly assigned to the intervention or control group, of whom 19 were excluded from the analysis. Median age was 53·8 years (IQR 46·5–63·3) in the intervention group and 53·7 years (46·5–63·2) in the control group. Interval cancer rates were 1·55 (95% CI 1·23–1·92) and 1·76 (1·42–2·15) per 1000 participants in the intervention and control group respectively, a non-inferior proportion ratio of 0·88 (95% CI 0·65–1·18; p=0·41). Descriptively, the intervention group had fewer interval cancers that were invasive (75 vs 89), T2+ (38 vs 48), or non-luminal A (43 vs 59) than the control group. Sensitivity was higher in the intervention group (80·5% [95% CI 76·4–84·2]) than the control group (73·8% [68·9–78·3]; p=0·031), an effect consistent across age and breast density, and for invasive cancer but not for in-situ cancer. Specificity was 98·5% (95% CI 98·4–98·6) for both groups (p=0·88).

Interpretation

AI-supported mammography screening showed consistently favourable outcomes compared with standard double reading, with a non-inferior interval cancer rate, fewer interval cancers with unfavourable characteristics, higher sensitivity, and the same specificity, while also reducing screen reading workload. These findings imply that AI-supported mammography screening can efficiently improve screening performance compared with standard double reading and may be considered for implementation in clinical practice."

Doomslayer: Progress Roundup - by Malcolm Cochran

AI-supported mammography screening results in fewer aggressive and advanced breast cancers, finds full results from first randomised controlled trial

AI support in breast cancer screening: Fewer missed cancer cases (original news release) "There were fewer cases of breast cancer between two screening rounds, and of the cancers that did develop, fewer were advanced or aggressive. The final results from Lund University's MASAI trial are now available, and they show further benefits of AI-supported breast cancer screening. The study has already shown that AI support in mammography screening contributes to a 29 percent increase in detected breast cancers compared to traditional screening."

Interval cancer, sensitivity, and specificity comparing AI-supported mammography screening with standard double reading without AI in the MASAI study: a randomised, controlled, non-inferiority, single-blinded, population-based, screening-accuracy trial

TimeVault, a genetically encoded system that records and stores transcriptomes within living mammalian cells

Amazing stuff!

"By converting a natural cell component called a vault into an mRNA time capsule, researchers have identified — and blocked — some of the mysterious gene activity that allows cancer cells to resist targeted drugs. These capsules, named ‘TimeVaults’, can grab onto a small amount of mRNA and store it for more than a week. Analyzing the contents of these capsules revealed some of the genetic drivers behind drug-resistant lung cancer cells known as persistors. When some overly active genes inside these cancer cells were inhibited, drugs became more effective against them."

"... To turn vaults into time capsules, Chen’s team engineered a vault protein in such a way that it recognizes and links to a molecular hallmark of mRNA molecules, thereby capturing the mRNA inside the vault. The production of this protein — the equivalent of hitting the ‘record’ button — is triggered by treating cells with a drug and stopped by withdrawing the drug.

With these modifications, the TimeVaults captured a small fraction of all of the mRNA molecules produced by a human cell line throughout a 24-hour period, and stored them for at least a week, ... The researchers found no sign that cells with TimeVaults behaved differently from regular vaults because of their cargo, nor that the barrel-shaped structures changed shape or size once filled ..."

From the abstract:

"Understanding how cells make decisions over time requires the ability to link past molecular states to future phenotypic outcomes.

We present TimeVault, a genetically encoded system that records and stores transcriptomes within living mammalian cells for future readout.

TimeVault leverages engineered vault particles that capture mRNA through poly(A) binding protein. We demonstrate that the transcriptome stored by TimeVaults is stable in living cells for over 7 days.

TimeVault enables high-fidelity transcriptome-wide recording with minimal cellular perturbation, capturing transient stress responses and revealing gene expression changes underlying drug-naive persister states in lung cancer cells that evade EGFR inhibition.

By linking past and present cellular states, TimeVault provides a powerful tool for decoding how cells respond to stress, make fate decisions, and resist therapy."

Nature Briefing: Cancer

A ‘time capsule’ for cells stores the secret experiences of their past "Scientists have transformed enigmatic cell structures, called vaults, into storage units for messenger RNA molecules." (no public access)

A genetically encoded device for transcriptome storage in mammalian cells (no public access)

Cancer cells use mitochondria stolen from immune cells to evade immune system

Amazing stuff! Cancer is history (soon)!

"Cancer cells use mitochondria stolen from immune cells to escape detection and spread. Researchers found that when cancer cells take on these mitochondria in mice, it both weakens the immune cells and triggers a molecular pathway in the cancer cells that help them fly under the immune system’s radar and invade lymph nodes. This beneficial molecular pathway was activated even when researchers disrupted the mitochondria’s ability to produce the energy-carrying molecule ATP. The findings could explain how cancer cells survive in lymph nodes, which are packed with immune cells that should be able to kill them."

From the highlights and abstract:

"Highlights

• Cancer cells hijack mitochondria from many immune cells

• Mitochondria loss by immune cells impairs innate and adaptive anti-tumor immunity

• Fusion of hijacked and endogenous cancer cell mitochondria triggers cGAS STING activation

• cGAS-STING activation promotes lymph node metastasis through type I interferon signaling

Summary

Although the immune system is a significant barrier to tumor growth and spread, established tumors evade immune attack and frequently colonize immune populated areas such as the lymph node. The mechanisms by which cancer cells subvert the tumor-immune microenvironment to favor spread to the lymph node remain incompletely understood.

Here, we show that, as a common attribute, tumor cells hijack mitochondria from a wide array of immune cells. Mitochondria loss by immune cells decreases antigen-presentation and co-stimulatory machinery, as well as reducing the activation and cytotoxic capacity of natural killer (NK) and CD8 T cells.

In cancer cells, the exogenous mitochondria fuse with endogenous mitochondria networks, leak mtDNA into the cytosol, and stimulate cGAS/STING, activating type I interferon-mediated immune evasion programs.

Blocking mitochondrial transfer machinery—including cGAS, STING, or type I interferon—reduced cancer metastasis to the lymph node. These findings suggest that cancer cells leverage mitochondria hijacking to weaken anti-tumor immunosurveillance and use the acquired mitochondria to fuel the immunological requirements of lymph node colonization."

Nature Briefing: Cancer

Cancer might evade immune defences by stealing mitochondria "Hijacking the energy-producing organelles from immune cells seems to help tumours in mice to infiltrate lymph nodes." (no public access)

Mitochondrial transfer from immune to tumor cells enables lymph node metastasis (no public access)

Graphical abstract