Tumor Immunology

Published today in Nature, Camilo Faust Akl et al. (Keith Ligon, Nino Chiocca, Francisco Javier Quintana) reveal that GBM co-opts TRAIL+ astrocytes to suppress anti-tumor immunity. The team identify a distinct subset of TRAIL+ astrocytes within the GBM tumor microenvironment that induces apoptosis in CD4⁺ and CD8⁺ T cells via a GBM-secreted IL-11 -> STAT3 signaling axis. These astrocytes also modulate microglia- and monocyte-derived TAMs, further amplifying T cell dysfunction. Notably, high TRAIL and IL-11 expression correlated with faster recurrence and worse survival in GBM patients, underscoring the clinical relevance of this pathway. Crucially, this immunosuppressive circuit can be therapeutically disrupted using an oHSV engineered to express an anti-TRAIL scFv—providing a compelling proof-of-concept for precision immunovirotherapy in GBM. Mass General Brigham, Harvard Medical School, Baylor College of Medicine, Boston University School of Medicine, Dana-Farber Cancer Institute, Broad Institute of MIT and Harvard, The University of Freiburg, McGill University

🌟 New Insights into Cancer Immune Evasion: Mitochondrial Transfer Mechanism Uncovered 🌟 Cancer cells deploy a variety of strategies to evade immune system attacks, but a groundbreaking study in Nature has uncovered a previously unknown mechanism involving mitochondrial DNA (mtDNA). Here's what researchers found: 🔬 Key Findings: 1️⃣ Mitochondria with mtDNA mutations are transferred from cancer cells to tumour-infiltrating lymphocytes (TILs). 2️⃣ These transferred mitochondria avoid mitophagy (mitochondrial degradation) due to mitophagy-inhibitory molecules. 3️⃣ TILs that acquire cancer cell mitochondria exhibit metabolic dysfunction, senescence, and impaired effector functions, weakening antitumour immunity. 4️⃣ The presence of mtDNA mutations in tumour tissues correlates with poorer outcomes for immune checkpoint inhibitor therapies in melanoma and non-small-cell lung cancer. https://lnkd.in/gBnf3Mhq ⚡ Why It Matters: This study highlights a novel cancer immune evasion strategy, where mitochondrial transfer undermines T cell function, providing potential biomarkers for therapy response and opening doors for innovative cancer immunotherapies. 🚀 Looking Ahead: Targeting the mitochondrial transfer process or reversing its effects could enhance the efficacy of existing immunotherapies and improve outcomes for cancer patients. 📚 Read more about these groundbreaking findings and their implications for the future of cancer treatment. #CancerResearch #Immunotherapy #TCellBiology #OncologyInnovation #Mitochondria #ImmuneEvasion

T Cell-based Immunotherapy: Boosting Mitochondrial Health for Superior Antitumor Responses One of the major barriers to successful T cell-based immunotherapies is T cell exhaustion driven in part by mitochondrial loss and dysfunction. This may reduce the effectiveness of adoptive T cell therapies, particularly against solid tumors. I was thrilled to see the latest innovation from Luca Gattinoni and his team at Regensburg who were finally able to publish their paper in CELL after years of effort ... and nearly a year and a half of feverish revisions at the journal (Baldwin, et al, Cell, 2024). When I first heard about the notion that the mitochondria of T cells could be replenished by bone marrow stromal cells (BMSCs) several years ago, I was incredulous. I thought the observations were an artifact of the methods. But early observations have now been buttressed by a slew of experiments from a multi-institutional team of investigators. The final product published last week leaves me convinced that BMSCs establish nanotubular connections with T cells, that act as highways to transfer healthy mitochondria into exhausted CD8+ T cells. This process enhances mitochondrial respiration and bioenergetic capacity, supercharging the T cells for improved function. Notably, Talin 2 on both donor and recipient cells is required for optimal transfer. Not only does mitochondrial transfer occur, but it has a major impact on a T cells developmental trajectory and fate. CD8+ T cells that received mitochondria showed increased expansion, more efficient tumor infiltration, and fewer signs of exhaustion. These boosted T cells mediated superior antitumor responses in the highly realistic pmel-1 mouse tumor model, ultimately prolonging survival. Undoubtedly, this approach is a long way from clinical development, but it could ultimately revolutionize the field of organelle medicine, opening new avenues for next-generation T cell therapies to combat not just hematologic malignancies but solid tumors as well. For those who take a long view of the future of immunotherapy and cellular rejuvenation, mitochondrial transfer may someday be part of the solution for enhancing T cell therapies! #CancerResearch #Immunotherapy #Mitochondria #TCellTherapy #AdoptiveTCellTherapy #OrganelleMedicine #Bioenergetics #TCellExhaustion #TumorMicroenvironment #CellTherapyInnovation

Cold tumors – cancers with little to no immune cell infiltration – represent one of oncology’s toughest challenges. These tumors evade the immune system, leaving patients with limited treatment hope. What if we could turn cold tumors “hot”? Published in Nature Communications, our breakthrough research at Insilico Medicine reveals a powerful new strategy: targeting ENPP1, a master regulator of immune evasion in cold tumors. Using our generative AI target discovery engine, we prioritized gastric carcinoma, colorectal carcinoma, and melanoma as indications for ENPP1 targeting beyond the well-established TNBC association. Our research demonstrates that inhibiting ENPP1: ✅ Reawakens the tumor microenvironment, enabling immune cell infiltration. ✅ Synergizes with checkpoint inhibitors to boost anti-tumor response.

Deciphering the intricate tumor-immune interactions within the microenvironment is crucial for advancing cancer immunotherapy. Here, we introduce mipDVP, an advanced approach integrating highly multiplexed imaging, single-cell laser microdissection, and sensitive mass spectrometry to spatially profile the proteomes of distinct cell populations in a human colorectal and tonsil cancer with high sensitivity. In a colorectal tumor—a representative cold tumor—we uncovered spatial compartmentalization of an immunosuppressive macrophage barrier that potentially impedes T cell infiltration. Spatial proteomic analysis revealed distinct functional states of T cells in different tumor compartments. In a tonsil cancer sample—a hot tumor—we identified significant proteomic heterogeneity among cells influenced by proximity to cytotoxic T cell subtypes. T cells in the tumor parenchyma exhibit metabolic adaptations to hypoxic regions. Our spatially resolved, highly multiplexed strategy deciphers the complex cellular interplay within the tumor microenvironment, offering valuable insights for identifying immunotherapy targets and predictive signatures. Interesting spatial proteomics study by Matthias Mann and larger team. https://lnkd.in/edAHnaWz 

🟥 Stressed tumors release immunosuppressive vesicles Follow for more 👉 #MD_Immunol https://lnkd.in/er5bRCGf 🔷️ EVs carry various proteins, nucleic acids, lipids, and small molecules that influence cells that ingest the EVs. 🔷️ Tumor-derived extracellular vesicles (TEVs) play a significant role in every stage of immunoediting, and their cargoes change from immune-activating in the early stages of immunoediting into immunosuppressing in the escape phase. 🔷️ Classical EVs are exosomes, microvesicles, and apoptotic bodies, while recent studies discovered autophagic EVs, stressed EVs, and matrix vesicles. 🔷️ Of note, cancer EVs play crucial roles in immunosuppression, immune evasion, and immunotherapy resistance. 🔷️ EVs modulate antigen presentation, and are able to induce T-cell apoptosis. 🔷️ Tumor-derived EVs regulate immune system cells’ functions. TEVs can promote tumor progression by suppression of innate and adaptive immune cells, as indicated in the left green panel. 👉figure A 🔷️ Thus, cancer EVs change hot tumors into cold ones. Moreover, cancer EVs affect nonimmune cells to promote cellular transformation, including epithelial-to-mesenchymal transition (EMT), chemoresistance, tumor matrix production, destruction of biological barriers, angiogenesis, lymphangiogenesis, and metastatic niche formation. 🔷️EVs can transmit pathological messages to healthy cells, causing ER stress. ER stress promotes the transmission of pathological messages to EVs, which are delivered to target cells and lead to disease development. 🔷️ Features of the tumour microenvironment (TME), such as hypoxia and nutrient deprivation, as well as oncogene mutations, cause endoplasmic reticulum (ER) stress in tumour cells and the induction of the unfolded protein response (UPR), which tumours exploit for their growth and survival. 🔷️ Tumor-infiltrating leukocytes (TILs) also experience ER stress, which can lead to immunosuppression. 🔷️ Tumor cell-released EVs or exosomes have been shown to promote a tumor-supporting environment in non-malignant tissue and, thus, benefit metastasis. 🔷️The EVs underlying mechanisms are numerous: loss of antigen expression, direct suppression of immune effector cells, exchange of nucleic acids, alteration of the recipient cells' transcription and direct suppression of immune cells. Consequently, tumour cells can subvert the host's immune detection as well as suppress the immune system. 🔷️ EVs, promote changes in the TME and immunosuppressive functions of immune cells (e.g., natural killer, dendritic cells, T and B cells, monocytes, macrophages) that allow tumor cells to establish and propagate. 🔷️ Despite the growing knowledge on EVs and on their roles in cancer and as modulators of the immune response/escape, the translation into clinical practice in this case need for more researches. #immunology  #extracellular #vesicles #immunosuppression #immunotherapy  #stressed

🟥 Why Has CAR-T Cell Therapy Repeatedly Failed in Solid Tumors? The success of CAR-T cell therapy in leukemia and lymphoma led researchers to believe that immune cells could potentially "eradicate" cancer. However, reality quickly dampened these hopes – CAR-T cell therapy has yet to achieve any significant breakthroughs in solid tumors. Most discussions attribute the reasons to three "old problems": insufficient target specificity, strong immunosuppression in the tumor microenvironment, and the difficulty of CAR-T cells entering tumor tissue. But these are merely superficial explanations. A less frequently mentioned, yet more crucial fact is that solid tumors are not a "target that can be eliminated by single cells," but rather a living, retaliatory ecosystem. In hematological malignancies, CAR-T cells face a single population of cells floating in the blood; in solid tumors, they enter a highly organized "society"—cancer cells, fibroblasts, blood vessels, immunosuppressive cells, and metabolic waste collectively create an extremely hostile environment for outsiders. More importantly, CAR-T cells quickly "lose their identity" after entering solid tumors. Continuous antigen stimulation, hypoxia, and nutrient deprivation transform them from "killers" into "exhausted bystanders." This is not an engineering problem, but a biological one. There's another reality that is not often discussed publicly: what solid tumors may need is not "stronger CAR-T cells," but a "reorganized immune system." This is precisely why people are turning to new approaches such as CAR-NK, CAR-M, in vivo CAR-T, microenvironment remodeling, and combined metabolic and vascular regulation. CAR-T cell therapy hasn't failed; it has simply revealed a deeper truth: cancer is not a single enemy, but a whole set of uncontrolled tissue structures. Therefore, the real breakthrough may come from our willingness to move beyond the "single-cell weapon" mindset. Follow us (www.csteamus.com) to learn more about the latest advancements and trends in immune cell and stem cell therapies. Reference [1] Giulia Escobar et al, Cell Rep Med 2025 (doi: 10.1016/j.xcrm.2025.102353)

Scientists have identified a hidden stress pathway in T cells that may explain why cancer immunotherapy sometimes fails. The study shows that exhausted T cells accumulate misfolded proteins, which trigger a destructive response called TexPSR. Unlike normal stress mechanisms that slow protein production, TexPSR accelerates it, causing toxic protein buildup that incapacitates the T cells. This overload prevents the immune system from attacking cancer effectively, limiting the success of therapies designed to harness T cells against tumors. In preclinical experiments, researchers blocked key elements of the TexPSR pathway. This intervention restored T cell function, allowing the immune cells to regain their ability to kill cancer cells. The approach significantly improved the effectiveness of immunotherapy in multiple cancer models, including lung, bladder, liver, and leukemia. The study also found that patients with higher TexPSR levels in their T cells were less likely to respond to treatment, suggesting this pathway could serve as both a marker and a therapeutic target. This discovery highlights the role of protein quality control in immune function and points toward new strategies to enhance T cell based therapies. By preventing the toxic buildup of misfolded proteins, scientists may be able to overcome T cell exhaustion and improve outcomes for patients receiving cancer immunotherapy in the future. Research Paper DOI: DOI: 10.1038/s41586-025-09539-1

This excellent review discusses the challenges in immune checkpoint therapies (ICT) for cancer treatment, specifically focusing on 'cold' tumours that lack effective anti-tumour T-cell responses. These tumours may be 'desert' tumours, impairing T cell generation and priming by antigen-presenting cells (APCs), or 'T-cell-excluded' tumours, where anti-tumour T cells are blocked from infiltrating the tumour mass. Understanding the mechanisms behind T-cell 'desertification' and 'exclusion' is crucial for developing novel immunotherapies that restore T cell generation and improve ICT efficacy. Combinatorial approaches targeting innate checkpoint regulators, autologous DCs vaccination, and mRNA vaccines show promise in enhancing T-cell priming and immunogenicity. Further research on tumour secretomes and genetic instabilities can lead to new insights for developing personalized and effective combinatorial immunotherapies in refractory cold tumours, complementing ICT and improving cancer patient responses. https://lnkd.in/euVy3FAf Regenerate response