Immune checkpoints (ICs) have traditionally been viewed as local inhibitory receptors that restrain T-cell activation and enable tumor immune escape. In this classical framework, pathways mainly function as key negative regulators within the tumor microenvironment by limiting T-cell receptor signaling, reducing effector T-cell activity, and maintaining immune tolerance. This concept has provided the mechanistic basis for IC blockade and profoundly reshaped cancer immunotherapy.
A review published in TransMed found recent evidence, however, has challenged the view that ICs actonly as local suppressive molecules in tumor immunity. Multisystem immune-related adverse events after ICI therapy indicate that checkpoint pathways also participate in systemic immune homeostasis.
In parallel, aberrant regulation of ICs has been observed in infections, autoimmune diseases, metabolic inflammation, cardiovascular inflammation, and tissue injury, suggesting that these molecules are embedded in broader inflammatory and metabolic networks rather than being restricted to tumor immune evasion. Inflammatory cytokines, metabolites, oxidative stress signals, and tissue-derived cues can regulate the expression and function of PD-1/PD-L1, CTLA-4, TIGIT, TIM-3, and LAG-3, thereby shaping immune exhaustion, tissue tolerance, and inflammatory persistence.
Based on these findings, this authors proposed that ICs should be understood as central regulatory hubs connecting local inflammatory microenvironments with systemic immune homeostasis. They also summarized the molecular basis of major IC pathways, their reciprocal interactions with inflammatory signals and ICI-associated toxicities.
By integrating checkpoint signaling with cytokine networks, metabolic reprogramming, and tissue-specific immune regulation, we aim to provide a conceptual framework for precision immunomodulation that balances therapeutic efficacy with immune safety,” says corresponding author Wangzhiqi Zhang.
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Contact author: Wangzhiqi Zhang, Faculty of Anesthesiology, Changhai Hospital, Naval Medical University, Shanghai, China, zwzq001031@smmu.edu.cn
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TransMed
Literature review
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Unlocking new horizons in immunity: The roles and mechanisms of immune checkpoints in inflammation regulation
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.