Antitumor immunity and immune-related toxicity during immune checkpoint inhibition: mechanistic overlap, tissue selectivity, and interventional evidence
- 1The Second Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China
Abstract
By relaxing immune tolerance, immune checkpoint inhibitors can restore antitumor responses but can also cause immune-related adverse events across multiple organs. Efficacy and toxicity occur together in some patients, yet this association does not mean that tissue injury is an unavoidable cost of effective antitumor immunity. Shared antigens, lymphocyte clones expanded across tissues, B-cell activation, and weakened immune regulation create overlap between tumor control and normal-tissue injury during immune priming and effector responses. Whether toxicity persists in a particular organ may be shaped by local antigen presentation, tissue residency, cellular interactions, epithelial barrier disruption, and amplification of innate inflammation, but direct support for these processes is strongest in colitis and remains less complete across other organs. Because residency programs also support tumor-reactive T cells, localization within an organ does not automatically preserve antitumor activity. Restricting organ homing, protecting tissue barriers, and targeting pathways such as IL-5, IL-6, JAK, and NLRP3 have shown potential to reduce toxicity in case series or animal models, but their effects on long-term tumor control remain insufficiently evaluated. Determining whether a treatment controls toxicity while preserving antitumor activity requires concurrent assessment, within the same cohort, of objective organ response, glucocorticoid exposure, resumption of immunotherapy, duration of tumor response, and survival. Current evidence supports further study of mechanisms that sustain toxicity within affected organs, but it is not yet sufficient to establish that most candidate strategies achieve durable, clinically meaningful separation of toxicity from antitumor benefit.
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BibTeX
@article{shi2026antitumor,
title = {{Antitumor immunity and immune-related toxicity during immune checkpoint inhibition: mechanistic overlap, tissue selectivity, and interventional evidence}},
author = {Chengyan Shi and Chunhai Li and Jun Yan},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1958441},
url = {https://doi.org/10.3389/fimmu.2026.1958441},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Antitumor immunity and immune-related toxicity during immune checkpoint inhibition: mechanistic overlap, tissue selectivity, and interventional evidence
AU - Chengyan Shi
AU - Chunhai Li
AU - Jun Yan
PY - 2026
DA - 2026/10/12
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1958441
UR - https://doi.org/10.3389/fimmu.2026.1958441
AB - By relaxing immune tolerance, immune checkpoint inhibitors can restore antitumor responses but can also cause immune-related adverse events across multiple organs. Efficacy and toxicity occur together in some patients, yet this association does not mean that tissue injury is an unavoidable cost of effective antitumor immunity. Shared antigens, lymphocyte clones expanded across tissues, B-cell activation, and weakened immune regulation create overlap between tumor control and normal-tissue injury during immune priming and effector responses. Whether toxicity persists in a particular organ may be shaped by local antigen presentation, tissue residency, cellular interactions, epithelial barrier disruption, and amplification of innate inflammation, but direct support for these processes is strongest in colitis and remains less complete across other organs. Because residency programs also support tumor-reactive T cells, localization within an organ does not automatically preserve antitumor activity. Restricting organ homing, protecting tissue barriers, and targeting pathways such as IL-5, IL-6, JAK, and NLRP3 have shown potential to reduce toxicity in case series or animal models, but their effects on long-term tumor control remain insufficiently evaluated. Determining whether a treatment controls toxicity while preserving antitumor activity requires concurrent assessment, within the same cohort, of objective organ response, glucocorticoid exposure, resumption of immunotherapy, duration of tumor response, and survival. Current evidence supports further study of mechanisms that sustain toxicity within affected organs, but it is not yet sufficient to establish that most candidate strategies achieve durable, clinically meaningful separation of toxicity from antitumor benefit.
SN - 1664-3224
ER -