Role of ISR in Cancer Immune Evasion

Recruitment of Immunosuppressive Cells and Immune Escape Recruitment of immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs), regulatory T cells (Tregs), and tumor-associated macrophages (TAMs), is an important mechanism by which tumors evade immune surveillance and suppress antitumor immunity. Cancer cells actively recruit these cells into the tumor microenvironment (TME) by secreting chemokines, cytokines, and growth factors. MDSCs are a heterogeneous population of cells that suppress T cell activation and promote tumor growth by producing arginase-1, nitric oxide, and reactive oxygen species (ROS). These factors inhibit T cell receptor (TCR) signaling, reduce effector T cell proliferation, and create a highly immunosuppressive microenvironment. Tregs play a crucial role in maintaining immune tolerance but are exploited by tumors to suppress antitumor immune responses. Tumors secrete CCL22 and other chemokines to attract Tregs, which suppress cytotoxic T lymphocyte (CTL) activity by producing suppressive cytokines, such as IL-10 and TGF-β. TAMs are often polarized to an M2-like phenotype within the TME, leading to immune evasion. M2-TAMs secrete VEGF, IL-10, and other factors that inhibit T cell function, promote angiogenesis, and support tumor progression. Their recruitment is mediated by tumor-secreted factors such as CSF-1 and CCL2. The cumulative effect of these immunosuppressive cells is to suppress antitumor immune responses, allowing tumors to grow uncontrollably. Targeting the recruitment and function of these cells is a promising strategy in cancer immunotherapy. Approaches include inhibiting chemokine pathways (e.g., CCR5, CCL2), reprogramming TAMs to an M1-like phenotype, or depleting Tregs and MDSCs to restore immune activity. By neutralizing the immunosuppressive influence of these cells, the TME can be reprogrammed to enhance the efficacy of immune checkpoint inhibitors and adoptive cell therapy. References [1] Yang Liu and Xuetao Cao, Journal of Molecular Medicine 2016 (DOI:10.1007/s00109-015-1376-x) [2] Yan Tie et al., Journal of Hematology & Oncology 2022 (doi: 10.1186/s13045-022-01282-8) #Immunotherapy #ImmuneEscape #CancerResearch #MDSCs #Tregs #TAMs #TumorMicroenvironment #CancerImmunology #OncologyUpdates #TargetedTherapy

The immune system is meant to protect the body by identifying and destroying harmful cells. However, new research reveals that in breast cancer, some immune cells can be reprogrammed to support tumour growth and spread. A recent review highlights how macrophages—key immune cells responsible for detecting and eliminating threats—are altered within the tumour microenvironment. Instead of attacking cancer cells, these modified macrophages assist them by promoting inflammation, stimulating blood vessel formation, and helping cancer cells invade surrounding tissues. This transformation enables tumours to grow more aggressively and eventually metastasize to distant organs. The study explains that breast cancer cells release signals that “re-educate” macrophages, shifting them from a protective role to one that supports disease progression. Conducted by researchers from Nagaland University and Banasthali Vidyapith, the review outlines common molecular pathways that regulate both macrophage differentiation and breast cancer metastasis. By understanding how tumours manipulate the body’s own defense system, scientists hope to develop therapies that target not only cancer cells but also the supportive environment that allows them to thrive. This approach could open new strategies to slow or prevent the spread of breast cancer. #BreastCancerResearch #TumourMicroenvironment #Macrophages #CancerMetastasis #Immunology #CancerBiology #TumourProgression #ImmuneEvasion #TranslationalMedicine #OncologyResearch

Our immune system relies on specialized defenders called T cells to hunt down and destroy microscopic threats. However, aggressive cancers and severe viruses often manage to survive by hiding in plain sight. Scientists have recently uncovered exactly how these diseases evade detection, discovering a molecular off-switch that effectively shuts down our natural biological defenses. A breakthrough study published in the Journal of Clinical Investigation identifies a specific protein known as TRAILshort. While researchers previously noticed the presence of this protein in HIV and certain tumors, its exact function remained elusive. The new research reveals that diseased cells use TRAILshort to actively disrupt the internal communication of our T cells. When a T cell approaches a diseased cell, TRAILshort triggers a molecular brake within the immune cell. This prematurely stops the T cell from launching an attack, neutralizing the threat response before it even begins. By using this protein to suppress the local immune environment, cancer cells and viruses can multiply completely unchecked by the body's natural security system. Understanding this evasion tactic fundamentally changes our approach to treating severe illnesses. Now that researchers know how tumors use TRAILshort as a biological shield, they can focus on developing targeted medications to block it. Neutralizing this protein has the potential to strip away the camouflage used by cancers, restore the immune system's fighting power, and significantly boost the effectiveness of modern immunotherapies. Journal of Clinical Investigation (2026). DOI: 10.1172/jci194449. Cancer doesn't hide — it hits the off-switch. New JCI 2026 study: tumors & HIV use protein TRAILshort to brake T cells and stop the attack before it starts. Blocking it could restore immune killing and boost immunotherapy. Jalali et al., JCI 2026. DOI: 10.1172/jci194449

#TME | Luring Tumour-killing #Tcells into #Cancer's LAIR | Targeting #LAIR1-mediated #Immunosuppression: a New Arm in the #Immunotherapy Arsenal | Open Access Study & Commentary* at The Journal of Clinical Investigation | Leukocyte-associated Ig-like receptor 1 (LAIR1) is a collagen-binding inhibitory immune receptor that negatively regulates cellular activation. In the latest issue of the JCI, Tao et al** show that LAIR1-inhibitory signaling plays an important role in immunosuppressive M2-like tumor-associated macrophages (TAMs) in aggressive brain tumors. LAIR1 KO, antibody blockade, and an immunotherapy that incorporates a LAIR1-inhibitory module into a chimeric antigen receptor (CAR) all led to increased antitumor activity by CAR T cells, reduced M2-like TAMs, altered collagen networks, and increased survival rates in mouse tumor models. These findings demonstrate an innovative immunotherapeutic approach for cancer that leverages LAIR1 inhibition to combat multiple tumor immune evasion strategies. *https://lnkd.in/eYMH2kmm **https://lnkd.in/eYg5S8uC Celentyx Ltd #immunooncology www.celentyx.com Professor Nicholas Barnes PhD, FBPhS Omar Qureshi Catherine Brady GRAPHICAL ABSTRACT | LAIR1-mediated suppression of the tumor immune response can be targeted by several strategies | (A) In tumors, LAIR1 expressed by macrophages binds collagen IV, promoting an M2-like phenotype and the production of immunosuppressive cytokines, which exhausts nearby T cells. Collagen IV production is increased within the TME, and CAR T cell penetration of the tumor is limited due to both exhaustion and the obstacle that the collagen network presents | (B) Treatments that block LAIR1 collagen binding (such as LAIR1 KO, antibodies against LAIR1, or LAIR1 antagonism via LAIR2 produced by the L2 module of the L2-8R-70CAR T cells) reduce M2 polarization and increase the production of immunostimulating cytokines, activating nearby T cells that attack and kill tumor cells, which are more accessible due to reduced collagen IV levels. These treatments increased survival in several different mouse tumor models |

Researchers have discovered how pancreatic tumors evade immune detection and developed a monoclonal antibody that counters this defense in preclinical models. Tumor cells exploit a natural “don’t attack” signal used by healthy cells by coating themselves in a sugar called sialic acid attached to a surface protein. This sugar shield binds to the immune receptor Siglec‑10, telling immune cells to stand down and allowing cancer cells to grow unchecked. The research team engineered antibodies to block the interaction between the sugar coated protein and the immune inhibitory receptor. In laboratory and mouse studies, the antibody disrupted this suppressive signal, reactivated immune cells such as macrophages, and slowed tumor growth compared with untreated controls. These findings indicate that targeting tumor immune evasion could enhance the body’s natural defenses against pancreatic cancer. Pancreatic cancer is highly resistant to immunotherapy and has low survival rates, making new approaches urgent. Although these results are currently limited to animal models, the study highlights a promising strategy to restore immune function by overcoming cancer’s camouflage and offers a potential pathway for future therapies. Research Paper 📄 PMID: 41182080

🟥 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

Metastatic breast cancer remains largely incurable, with survival rates dropping from over 90% for localized disease to around 25% for distant metastases. Understanding how the tumor microenvironment changes during this transition is critical for developing better treatments. Recent research from Oregon Health & Science University provides new insights into these cellular transformations. Methods: Researchers analyzed single-cell RNA sequencing data from 23 female patients with estrogen receptor-positive (ER+) breast cancer—12 with primary tumors and 11 with metastases across multiple sites including liver, bone, lymph nodes, and skin. This comprehensive approach examined nearly 100,000 individual cells to understand how different cell types behave in primary versus metastatic settings. Results: The study revealed several key differences between primary and metastatic tumors: - Immune System Changes: Metastatic tumors showed a shift toward immunosuppression, with increased numbers of exhausted T cells and regulatory T cells that dampen immune responses. Primary tumors maintained more pro-inflammatory immune cell populations. - Macrophage Polarization: Primary tumors contained more immune-activating macrophages (FOLR2+ and CXCR3+), while metastatic sites were dominated by tumor-promoting macrophages expressing CCL2, SPP1, and MMP9—proteins associated with invasion and immune suppression. - Metabolic Reprogramming: T cells in primary tumors relied on glycolysis for energy, supporting rapid immune responses. In metastatic sites, T cells shifted to fatty acid metabolism and oxidative phosphorylation, potentially contributing to immune exhaustion. - Stromal Remodeling: Cancer-associated fibroblasts changed from inflammatory and antigen-presenting types in primary tumors to matrix-remodeling types in metastases, creating an environment that supports tumor growth and blocks immune infiltration. - Cellular Communication: The study identified a marked decrease in communication between tumor cells and immune cells in metastatic tissues, contributing to immune evasion. Conclusions: This research demonstrates that metastatic progression involves coordinated changes across multiple cell types, not just cancer cells themselves. The tumor microenvironment becomes increasingly immunosuppressive through specific cellular reprogramming events. These findings suggest potential therapeutic targets, including the TNF-α/NF-κB pathway that was more active in primary tumors, and specific macrophage subtypes that could be targeted to restore immune function in metastatic disease. Paper and research by @Furkan Ozmen and larger team

IRGQ-mediated autophagy in MHC class I quality control promotes tumor immune evasion:- •The autophagy-lysosome system directs the degradation of a wide variety of cargo and is also involved in tumor progression. Here, we show that the immunity-related GTPase family Q protein (IRGQ), an uncharacterized protein to date, acts in the quality control of major histocompatibility complex class I (MHC class I) molecules. IRGQ directs misfolded MHC class I toward lysosomal degradation through its binding mode to GABARAPL2 and LC3B. In the absence of IRGQ, free MHC class I heavy chains do not only accumulate in the cell but are also transported to the cell surface, thereby promoting an immune response. Mice and human patients suffering from hepatocellular carcinoma show improved survival rates with reduced IRGQ levels due to increased reactivity of CD8+ T cells toward IRGQ knockout tumor cells. Thus, we reveal IRGQ as a regulator of MHC class I quality control, mediating tumor immune evasion. #highlights:- •IRGQ is identified as a novel autophagy receptor. •Structures of IRGQ in complex with GABARAPL2 or LC3B show distinct binding modes. •IRGQ acts in the quality control of misfolded MHC class I to degrade it through autophagy. •IRGQ impacts CD8+ T cell immunity in human and murine hepatocellular carcinoma.

🧫✨ CD47 targeting is such an interesting strategy in cancer immunotherapy because it focuses on one of the ways tumor cells avoid being eliminated by the innate immune system. CD47 is often referred to as a “don’t eat me” signal. When CD47 on the surface of a cancer cell binds to SIRPα on a macrophage, it delivers an inhibitory signal that suppresses phagocytosis. So even when a macrophage recognizes an abnormal cell, that interaction can prevent it from actually engulfing and clearing it 🛑 This is one of the clearest examples of how cancer cells do not just grow uncontrollably, they also actively develop mechanisms of immune evasion. What makes this pathway so important therapeutically is that blocking CD47 can interrupt that inhibitory signaling. With an anti CD47 monoclonal antibody, the macrophage is no longer receiving the same anti phagocytic signal, which can restore its ability to engulf tumor cells 🧬🔬 From an immunology perspective, I think this is especially fascinating because it highlights the role of the innate immune system in cancer treatment. A lot of people immediately think of T cells when they think about immunotherapy, but macrophages are also major players in the antitumor response 🌟 CD47 targeted therapy really shows how effective treatment can come from understanding very specific receptor ligand interactions at the tumor immune interface. When you block one checkpoint, you can shift the balance back toward immune mediated tumor clearance. It is such a good reminder that cancer progression is not only about proliferation, it is also about whether tumor cells can successfully avoid being recognized and removed by the immune system 💥 #CancerImmunotherapy #CD47 #Immunology #CancerBiology #Macrophages #InnateImmunity #ImmuneEvasion #Oncology #CancerResearch #BiomedicalScience #WomenInSTEM *Downloaded from BioRender for Educational Purposes*