Abstract
Tumorigenesis embodies the formation of a heterotypic tumour microenvironment (TME) that, among its many functions, enables the evasion of T cell-mediated immune responses. Remarkably, most TME cell types, including cancer cells, fibroblasts, myeloid cells, vascular endothelial cells and pericytes, can be stimulated to deploy immunoregulatory programmes. These programmes involve regulatory inducers (signals-in) and functional effectors (signals-out) that impair CD8+ and CD4+ T cell activity through cytokines, growth factors, immune checkpoints and metabolites. Some signals target specific cell types, whereas others, such as transforming growth factor-β (TGFβ) and prostaglandin E2 (PGE2), exert broad, pleiotropic effects; as signals-in, they trigger immunosuppressive programmes in most TME cell types, and as signals-out, they directly inhibit T cells and also modulate other cells to reinforce immunosuppression. This functional diversity and redundancy pose a challenge for therapeutic targeting of the immune-evasive TME. Fundamentally, the commonality of regulatory programmes aimed at abrogating T cell activity, along with paracrine signalling between cells of the TME, suggests that many normal cell types are hard-wired with latent functions that can be triggered to prevent inappropriate immune attack. This intrinsic capability is evidently co-opted throughout the TME, enabling tumours to evade immune destruction.
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Acknowledgements
D.H. acknowledges support from the Ludwig Institute for Cancer Research. O.M. is supported by the University Hospital of Geneva. M.J.P. is supported by the Swiss Institute for Experimental Cancer Research (ISREC) Foundation and the Ludwig Institute for Cancer Research. We thank M. de Palma, C. Jandus and M. Cuendet for comments and suggestions.
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None of the research results reviewed and discussed here reflect bona fide competing interests. In the interest of full disclosure, D.H. currently serves on the scientific advisory boards of Pfizer Oncology, Opna Bio, 4D Molecular Therapeutics and Cellestia, and is a founder of Opna Bio, which has licensed an EPFL patent describing the RNA-binding protein FMRP as a new cancer target. O.M. has served as an adviser for Roche, Novartis, GSK, BMS, MSD, Regeneron, Pierre-Fabre, Merck and Amgen, and is a scientific board member of Cellula Therapeutics. M.J.P. has served as an adviser for AstraZeneca, ImmuneOncia, LegoChem Bio, MaxiVax, Merck, Molecular Partners, Third Rock Ventures, Tidal and Unikum.
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Glossary
- Autophagy
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A cellular process that degrades and recycles damaged organelles, proteins and other cellular components through the lysosomal pathway. Autophagy is crucial for maintaining cellular homeostasis and responding to stress.
- Cachexia
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A complex metabolic syndrome associated with underlying illness, characterized by severe weight loss, muscle atrophy and fatigue. Cachexia is commonly seen in cancer, but also in other chronic inflammatory diseases.
- Chaperone-mediated autophagy
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A selective form of autophagy in which specific cytosolic proteins are recognized by chaperone proteins and directly translocated across the lysosomal membrane for degradation.
- Ferroptosis
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A form of regulated cell death driven by the accumulation of lipid peroxides resulting in oxidative damage to cell membranes. Ferroptosis is dependent on iron, with iron catalysing the formation of lipid peroxides.
- High endothelial venules
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(HEVs). Specialized blood vessels that facilitate the entry of lymphocytes from the blood into tissue. HEVs are found in lymphoid organs such as lymph nodes, but can be induced in and around tumours to facilitate the infiltration of T cells.
- Interstitial fluid pressure
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The pressure exerted by the fluid present in the spaces between cells. This pressure is involved in fluid exchange between blood vessels and tumour tissues and is exacerbated by the leaky angiogenic vasculature in many tumours and by the dense packing of proliferating cancer cells and accessory cells into the tumour microenvironment.
- Neutrophil extracellular traps
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(NETs). Web-like structures composed of DNA and antimicrobial proteins released by neutrophils during a process called NETosis. NETs in the tumour milieu can also exacerbate inflammation, potentially contributing to tumour progression.
- Oncogene-induced senescence
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A cell-cycle arrest triggered by the activation of oncogenes. It acts directly as a tumour-suppressive mechanism by preventing the uncontrolled proliferation of cells with oncogenic mutations, although the induced senescence-associated secretory programme can have paracrine effects that are alternatively tumour-promoting and immunosuppressive or tumour-antagonizing and immunostimulatory.
- Secondary lymphoid organs
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Organs where immune responses are initiated and organized, such as lymph nodes and the spleen. Secondary lymphoid organs provide environments for the activation and proliferation of lymphocytes.
- Senescence-associated secretory programme
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(SASP). A feature of senescent cells, characterized by the secretion of various cytokines, growth factors, proteases and other molecules. The SASP can variously elicit paracrine immunosuppressive and tumour-promoting effects or, alternatively, immunostimulatory tumour-impairing effects.
- Tertiary lymphoid structures
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(TLSs). Ectopic lymphoid formations that arise in non-lymphoid tissues, including solid tumours, in response to chronic inflammation. TLSs resemble secondary lymphoid organs and facilitate local immune responses by organizing adaptive immune cells.
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Hanahan, D., Michielin, O. & Pittet, M.J. Convergent inducers and effectors of T cell paralysis in the tumour microenvironment. Nat Rev Cancer 25, 41–58 (2025). https://doi.org/10.1038/s41568-024-00761-z
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DOI: https://doi.org/10.1038/s41568-024-00761-z
