---
title: "Understanding Antitumor Immunity and Immune-Related Toxicity in Checkpoint Inhibition"
id: "frontiers-in-immunology-19-antitumor-immunity-and-immune-related-toxicity-during-immune-checkpoint"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-antitumor-immunity-and-immune-related-toxicity-during-immune-checkpoint"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1958441"
published_at: "2026-10-12T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Understanding Antitumor Immunity and Immune-Related Toxicity in Checkpoint Inhibition
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-19-antitumor-immunity-and-immune-related-toxicity-during-immune-checkpoint
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1958441)
- **Published At:** 2026-10-12T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- Immune checkpoint inhibitors restore antitumor responses but can cause organ-specific immune-related adverse events (irAEs). - Shared antigens and lymphocyte clones contribute to both tumor control and tissue injury, influenced by local factors. - Strategies like targeting cytokines and specific pathways may mitigate toxicity, but long-term efficacy is unclear. - Interventional and mechanistic studies provide varying evidence, with localized inflammation processes critical for understanding outcomes. - Current data support the need for thorough evaluations of treatment strategies to distinguish antitumor efficacy from toxicity.
## Clinical Analysis & Structured Key Points
Frontiers | Antitumor immunity and immune-related toxicity during immune checkpoint inhibition: mechanistic overlap, tissue selectivity, and interventional evidence REVIEW article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1958441 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Part of a Research Topic Community Series in Reducing Adverse Effects of Cancer Immunotherapy: Volume IV Submission open 20k views 14 articles Editor & Reviewers Edited by C M Cleber Machado-Souza Reviewed by Q S Qingxiao Song W Y WenQing Yang Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article Table 1 Mechanistic processes linking antitumor immunity and immune-related toxicity: overlap, tissue restriction, and therapeutic implications. View in article Table 2 Representative interventions for immune-related adverse events and available evidence regarding antitumor outcomes. View in article REVIEW article Front. Immunol. , 12 October 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1958441 Antitumor immunity and immune-related toxicity during immune checkpoint inhibition: mechanistic overlap, tissue selectivity, and interventional evidence C S Chengyan Shi C L Chunhai Li J Y Jun Yan * The Second Department of Oncology, The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, Heilongjiang, China Article metrics View details 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. 1 Introduction Immune checkpoint inhibitors (ICIs) enhance antitumor T-cell responses by blocking inhibitory signals such as CTLA-4, PD-1, or PD-L1. The same treatments can disrupt peripheral tolerance and cause immune-related adverse events (irAEs) involving the skin, gastrointestinal tract, liver, lungs, endocrine glands, neuromuscular system, and heart. Current guidelines stratify recommendations for ICI interruption, glucocorticoids, and subsequent immunosuppression by the affected organ and severity, although many recommendations still rely largely on expert consensus and nonrandomized evidence ( 1 ). The association between irAEs and tumor outcomes is not uniform. An analysis of 9521 patients from 14 atezolizumab trials found that grade 1–2 irAEs were associated with longer overall survival, whereas grade 3–4 irAEs did not show the same overall benefit. Severe pneumonitis and colitis were associated with poorer survival, and the direction of the association varied by organ and severity ( 2 ). Thus, irAEs are not a uniform surrogate for efficacy, and whether toxicity control alters antitumor immunity must be evaluated directly in treatment studies. Mechanistic studies suggest that tumors and affected organs may share antigens or T-cell clones, but organ injury also depends on local resident cells, spatial cellular proximity, tissue barriers, and myeloid inflammation. Some processes contribute to both tumor control and tissue injury, whereas others may become more important after immune cells enter a particular organ. Systemic immune suppression, modulation of tissue recruitment, interruption of local effector pathways, and barrier protection therefore cannot be assumed to have equivalent effects on antitumor immunity. The most direct tissue-mechanistic and interventional data currently come from colitis and myocarditis. Observations from skin, lung, liver, kidney, endocrine, neurologic, eosinophilic, and transplant-associated toxicities constitute organ-specific evidence rather than interchangeable support for a universal model ( Figure 1 ). Figure 1 Shared immune activation and divergence into tumor-directed immunity and immune-related tissue injury during immune checkpoint inhibition. Checkpoint blockade promotes immune priming, reduces peripheral tolerance, and expands lymphocyte clones that may contribute to both tumor-directed immunity and normal-tissue injury. In the tumor branch, antitumor activity depends on tumor-antigen recognition, intratumoral localization, and cytotoxic function. In affected tissues, recruitment is followed by local antigen presentation, tissue residency, inflammatory cellular interactions, and myeloid or innate inflammatory amplification that may contribute to tissue injury and persistence. These processes may overlap in time and are not uniformly established across organs. Detection of shared T-cell clonotypes across tumors and affected tissues establishes sequence overlap but does not, by itself, demonstrate shared antigen specificity or pathogenicity. Evidence for the depicted local persistence mechanisms is strongest in colitis and selected cardiac studies and should not be generalized uniformly across irAEs. Here, selective immunomodulation denotes a clinically testable treatment property rather than a presumed feature of a tissue-restricted or downstream target. Mechanistic or anatomical restriction provides a rationale for selectivity, but is insufficient to infer tumor sparing because tumor-cell JAK–IFN-γ integrity, tissue-residency programs, and IL-6-linked inflammatory circuits can also shape tumor immunity and responses to checkpoint blockade ( 3 – 5 ). A clinically credible claim therefore requires, in the same treated cohort, meaningful toxicity improvement—preferably an objective organ response with reduced glucocorticoid or additional immunosuppressive exposure and ICI continuation or resumption when appropriate—together with longitudinal oncologic assessment, including response durability, subsequent progression, progression-free survival, and overall survival. The effort to separate graft-versus-host disease (GVHD) from graft-versus-leukemia (GVL) provides a useful conceptual precedent. In allogeneic hematopoietic cell transplantation, tissue-directed trafficking, local treatment, and tissue-tolerance strategies are being studied to limit normal-tissue injury while retaining immune activity in the bone marrow, but reliable clinical separation has not been established ( 6 ). The analogy is incomplete: GVHD/GVL is driven by donor alloreactivity in a transplant setting, whereas ICI therapy reinvigorates endogenous immunity against solid tumors. GVHD/GVL provides precedent for testing tissue-directed approaches, but it does not establish that analogous strategies during ICI treatment will preserve antitumor immunity. Preservation of antitumor control must still be demonstrated directly. 2 Shared antigens, clonal expansion, and T–B-cell cooperation create partial mechanistic overlap 2.1 Shared antigens and T-cell clones in tumors and affected tissues When tumors and normal tissues express identical or related antigens, ICI-expanded T cells may recognize both. In a prospective cohort of patients with non-small-cell lung cancer treated with anti-PD-1 therapy, 25 of 73 patients developed autoimmune skin toxicity. Shared antigens were identified in tumors and affected skin, and the corresponding antigens stimulated CD8 or CD4 T cells in vitro . These findings support a possible role for shared antigens in skin toxicity, but they arose from one tumor type and one affected organ and cannot explain other irAEs ( 7 ). In 2 patients who developed fatal myocarditis, myositis, and rhabdomyolysis after ipilimumab plus nivolumab, high-frequency T-cell clones in the myocardium were also found in the tumor and skeletal muscle. The tumors expressed muscle-associated antigens, providing a candidate explanation for attack on muscle tissue by tumor-activated clones ( 8 ). The presence of identical T-cell receptor (TCR) sequences across tissues nevertheless has several possible explanations: a clone may recognize the same antigen in both sites, cross-react with related antigens, or simply be detected in both samples because of sampling and expansion biases affecting a high-frequency clone. TCR-sequencing studies show that estimates of shared clonotypes are influenced by sample size, tissue compartment, sampling time, and batch. Evidence for pathogenicity therefore progresses beyond sequence overlap in several steps. Clonal overlap establishes only sequence identity. Identification of a candidate shared or cross-reactive antigen narrows the mechanism, and functional stimulation of the relevant clone establishes antigen responsiveness. Spatial localization beside injured target cells and a quantitative association with tissue damage strengthen biological relevance, but causal support requires perturbation showing that removal or blockade of the clone or pathway reduces injury while appropriate tumor and unaffected-tissue controls exclude bystander expansion ( 7 – 9 ). Few human irAE studies traverse this sequence from clonotype to causal tissue injury. Until the pathogenic clones and their antigens are defined, the consequences of removing a particular T-cell population for tumor control will remain difficult to predict. The same clone may also acquire different functions after entering different tissues. Local antigen presentation, TGF-β and IL-15 signaling, inhibitory receptors, cell adhesion, oxygen availability, and nutrient conditions all influence T-cell residency, survival, and effector state ( 4 ). Resident T cells within tumors can contribute to treatment responses, while resident cells can be reactivated in cutaneous and gastrointestinal irAEs. Blocking tissue entry or maintenance of residency could therefore reduce toxicity but also deplete intratumoral effector cells. Downstream signals that predominate in the affected organ may provide more anatomically restricted targets than the resident phenotype itself, but their effects on antitumor immunity still require direct assessment. 2.2 B-cell activation, Tph-like help, and regulatory T-cell restraint Peripheral B-cell changes can emerge during the first treatment cycle after combined CTLA-4 and PD-1 blockade. These changes include a reduction in total B cells, increases in CD21^low B cells and plasmablasts, and expansion of selected clones. They precede clinical irAEs and are associated with the frequency and timing of subsequent high-grade irAEs ( 10 ). Peripheral B-cell changes may therefore help identify patients at increased risk, but the available observational associations do not show whether preventive B-cell-directed intervention is beneficial. Patient samples, coculture experiments, and humanized mouse models further showed that combined checkpoint blockade expanded an ICOS-positive peripheral helper T-cell-like population and promoted responses involving CD21^low CD11c-positive B cells and plasmablasts. ICOS-positive CD4 T cells enhanced plasmablast differentiation and IgG production, and this response increased after regulatory T-cell depletion. Among patients who did not develop high-grade irAEs, a higher proportion of ICOS-positive CD4 T cells acquired a regulatory phenotype after treatment ( 11 ). The balance between effector T–B-cell cooperation and regulatory restraint may track toxicity risk more closely than expansion of either cell population alone. ICOS-positive T cells and B-cell responses may also contribute to antitumor immunity, making wholesale depletion of these populations unlikely to be selective. The available data are better suited to early risk identification and toxicity phenotyping than to direct therapeutic targeting. Blocking a specific helper signal or augmenting regulatory T cells would have a clearer mechanistic basis only if humoral immunity or T–B-cell interactions were shown to dominate a defined toxicity subtype. 2.3 TREX1 deficiency links autoimmune susceptibility and antitumor responses to shared immune programs Genetic studies in mice showed that persistent loss of the cytosolic DNA exonuclease TREX1 caused multiorgan CD8 T-cell infiltration, myocarditis, and Sjögren-like manifestations while enhancing CD8 T-cell-driven antitumor immunity. By contrast, inducible deletion in adulthood was better tolerated and retained antitumor activity ( 12 ). Innate DNA sensing and adaptive T-cell effector responses can therefore influence both autoimmune susceptibility and tumor control, while the timing of intervention and host state alter the resulting phenotype. This mouse model illustrates how host background and the timing of immune activation can shift the balance between self-tissue injury and tumor control. It is not equivalent to patient-derived irAE evidence, but it supports distinguishing the generation of effective antitumor clones from the persistence of injury in nonmalignant organs. The latter also depends on survival, effector, and tissue-damaging signals acquired after cells enter the affected organ. 3 Resident immunity, barrier disruption, and innate inflammation in the colon and heart 3.1 IFN-γ-producing CD8 tissue-resident memory T cells in ICI colitis Single-cell analysis of ICI colitis identified expanded cytotoxic and proliferative CD8 T-cell states, with TCR evidence that a substantial fraction of colitis-associated cells arose from tissue-resident populations ( 13 ). In an independent study, multiparameter flow cytometry, tissue imaging, and transcriptomic analyses comparing ICI colitis, ICI-treated patients without colitis, ulcerative colitis, and healthy controls identified IFN-γ-producing CD8 tissue-resident memory T (TRM) cells as a prominent activated population. Their activation correlated with clinical and endoscopic severity, and ICI colitis differed from ulcerative colitis in immune and epithelial signaling. On the basis of this pathway, 1 patient with refractory disease was treated with the JAK inhibitor tofacitinib and achieved remission, but a single therapeutic case cannot establish general efficacy or tumor safety ( 14 ). Gut entry and mucosal persistence are related but distinct processes: α4β7 and CCR9 contribute to intestinal homing, whereas local cytokines and adhesion programs support retention and tissue adaptation ( 15 ). TRM cells can rapidly release effector molecules after local stimulation. Systemic exposure to an ICI therefore need not produce uniform tissue injury; pre-existing resident cells, chemotactic signals, and the local stromal state may jointly determine whether persistent inflammation develops in the intestine ( 13 , 14 ). Tumor-reactive T cells can also adopt residency programs ( 4 ), so TRM cells are not intrinsically safe therapeutic targets. Cellular interactions, downstream cytokines, or barrier responses that predominate in the affected organ may provide more anatomically restricted targets, although anatomical restriction alone does not show that antitumor immunity will be preserved. 3.2 ICI-bound T cells form distinct cellular niches in colonic tissue Tracking of ICI-bound T cells, single-cell sequencing, and subcellular-resolution spatial transcriptomics in blood and intestinal tissue from patients with ICI colitis identified ICI-bound Tfh, Tph, Th17, Treg, and HAVCR2-positive CD8 T cells. These cells were enriched in distinct niches within colitic tissue, and niche composition also distinguished ICI colitis from ulcerative colitis ( 16 ). Because checkpoint inhibitors bound multiple effector, helper, and regulatory T-cell populations, drug binding itself did not show that the bound cells were pathogenic. Spatial proximity can reveal whether T cells form local inflammatory units with epithelial, myeloid, or B cells, but colocalization alone does not identify which population sustains tissue injury ( 16 ). Genetic, pharmacologic, or ex vivo perturbation is needed to separate pathogenic circuits from changes secondary to inflammation. 3.3 MLCK1-dependent tight-junction leak amplifies intestinal injury Studies using human ICI colitis samples, organoids, and tumor-bearing mice showed that T-cell-derived tumor necrosis factor activated an MLCK1-dependent tight-junction leak pathway and disrupted the intestinal epithelial barrier. Genetic deletion of MLCK or pharmacologic disruption of the MLCK1–FKBP8 interaction with epicatechin reduced colitis and barrier injury in model systems without attenuating the antitumor effect of ICIs ( 17 ). This study localized a potentially tractable process to the epithelial response to inflammatory signaling rather than to direct suppression of antitumor T cells. Epicatechin was used mainly as a protective intervention concurrent with ICI treatment, and tumor outcomes were based primarily on short-term volume and terminal weight. The experiments therefore did not establish whether existing colitis could be reversed or whether long-term tumor control would be preserved. Effective exposure, target specificity, pharmacokinetics, and clinical safety also remain unconfirmed in patients with ICI colitis, leaving barrier protection as a preclinical candidate strategy. 3.4 The NLRP3 inflammasome in ICI-associated cardiac injury In models of ICI-associated cardiac injury, the NLRP3 inflammasome inhibitor MCC950 reduced the infiltration of pathogenic macrophages and cytotoxic and activated T cells and improved cardiac function. In a concurrent-treatment experiment using B16F10 tumor-bearing mice, reduced cardiac injury was accompanied by lower tumor volume and weight ( 18 ). Publicly available peripheral-blood single-cell data also showed increased NLRP3 and IL1B expression in monocytes from patients with ICI myocarditis, although this does not substitute for functional validation in human myocardium. The investigators separately initiated MCC950 after cardiac injury had developed; tumors were not implanted in this experiment because of animal-welfare constraints. The first experiment provides a joint cardiac–tumor signal during preventive or concurrent intervention, whereas the second addresses only whether established cardiac injury can be improved. These experiments cannot be combined as evidence that treatment of established myocarditis preserves tumor control ( 18 ) ( Table 1 ). Table 1 Mechanism Principal cells or pathway Antitumor role Role in irAEs Evidence Basis for organ restriction Therapeutic implication Key boundary Checkpoint release and tolerance disruption CTLA-4, PD-1
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