Decoding Innate T Cell Functionality in Tumor Immunity and Therapeutic Response

Abstract

Innate T cells, including invariant natural killer T (iNKT) cells, mucosal-associated invariant T (MAIT) cells, and γδ T cells, bridge innate and adaptive immunity through rapid responses to nonpeptide antigens, metabolites, and stress-associated signals. In cancer, these populations can promote tumor surveillance through cytotoxicity, type 1 cytokine production, tissue-resident immune monitoring, and activation of broader antitumor networks. However, their functions are highly context dependent. Within suppressive tumor microenvironments, tumor-infiltrating unconventional T cell compartments may contain developmentally programmed innate-like subsets together with recruited or locally differentiated cells displaying dysfunctional, regulatory, or IL-17-associated features that support myeloid cell recruitment, chronic inflammation, immune evasion, and therapy resistance. This review discusses the major recognition pathways, functional states, microbiota- and metabolite-dependent regulation, and therapeutic targeting of iNKT, MAIT, and γδ T cells in cancer. We further highlight emerging strategies to harness these cells through endogenous activation, combination immunotherapy, and engineered cell platforms while limiting tumor-promoting inflammatory programs and treatment-associated toxicity.