Authors
Jiazhi Yi, Shuyun Wu, Hongxia He
Published in
Apoptosis : an international journal on programmed cell death. Volume 31. Issue 12. Nov 11, 2026. Epub Nov 11, 2026.
Abstract
Programmed cell death (PCD) is a metabolically controlled decision point that shapes antitumor immunity, and its dysregulation is increasingly recognized as a central driver of immune‑checkpoint‑blockade (ICB) resistance in microsatellite‑stable (MSS) colorectal cancer (CRC). Mechanistically, this review focuses on the cell-type-specific molecular switches that determine whether PCD drives immunosuppression or immunogenic cell death. In this review, we propose a unified mechanistic framework centered on a dual PCD imbalance: dysregulated tumor microenvironment (TME) metabolism predominantly activates pyroptosis, ferroptosis, and apoptosis in antitumor immune cells-an immunosuppressive outcome that depends on cell type, stimulus, and tissue context-while tumor-intrinsic epigenetic silencing preferentially abolishes necroptosis, cuproptosis, and PANoptosis in tumor cells, blocking DAMP release and de novo T cell priming. Four stromal and immune subsets drive distinct metabolic cascades: cancer‑associated fibroblasts fuel lactate‑mediated dendritic cell pyroptosis and CD8⁺ T cell ferroptosis; tumor‑associated macrophages amplify lipid‑peroxidation‑driven ferroptosis; myeloid‑derived suppressor cells induce T cell apoptosis via amino acid deprivation; and regulatory T cells exploit kynurenine and adenosine signaling to eliminate antitumor lymphocytes. These cellular insults are reinforced by soluble amplifiers (TGF‑β, IL‑10/IL‑35, adenosine) and VEGF‑driven hypoxia, forming a redundant immunosuppressive network. We hypothesize that this dual PCD imbalance-sustained suppressive PCD of antitumor immune cells combined with silenced immunogenic PCD of tumor cells-locks MSS CRC in an immune‑cold state and explains why single‑agent therapies consistently fail. Accordingly, CMS‑stratified combinatorial regimens that concurrently restrain suppressive PCD and awaken immunogenic tumor cell death may be required to overcome ICB resistance. Emerging approaches spanning spatial multi‑omics, gut microbiota targeting, and myeloid checkpoint inhibition provide opportunities to remodel the cold TME and translate this metabolic‑PCD framework into subtype‑tailored precision immunotherapy for MSS CRC. This dual-PCD-imbalance framework is a testable working hypothesis requiring further combinatorial validation in MSS-CRC-relevant systems.
PMID:
43013153
Bibliographic data and abstract were imported from PubMed on 12 Nov 2026.
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