From sentinels to soldiers: tissue-resident cells for next-generation immunotherapy.

Tissue-resident immune cells are specialized populations that survey peripheral tissues independently of circulating input. Their strategic positioning, persistence, and capacity for rapid local response make them key mediators of durable antitumor immunity. Although this biology has been most extensively defined in CD8⁺ tissue-resident memory T (TRM) cells, tissue residency is increasingly recognized as a broader principle of peripheral immunity, extending to CD4⁺ TRM cells, tissue-resident NK cells, and myeloid populations. This review provides an integrative framework tracing tissue-resident biology from its ontogeny to its therapeutic frontier. We propose that TRM differentiation is shaped by the interplay between priming signals and tissue niches, with priming generating residency-poised states that are resolved into stable phenotypes by local tissue cues. We encompass a framework of canonical niches across barrier and nonbarrier tissues, identify shared instructive axes, and extend this classification to noncanonical reservoirs such as bone marrow. We further examine the metabolic dimension of tissue residency: fatty acid oxidation, purinergic adaptation, and hypoxic specialization as an active and instructible program with direct manufacturing implications for cellular immunotherapy. We propose tumors as pathological noncanonical niches in which the mechanisms of tissue retention are preserved but the effector identity is lost, and address how TRM cells nonetheless emerge as critical determinants of immunosurveillance and checkpoint blockade responsiveness. We conclude that integrating tissue-residency principles into next-generation immunotherapy is not a minor refinement but a necessary shift to achieve durable responses in solid tumors.