Innate-like T Cell Biology in the Tumor Microenvironment Implications for Cancer Immunotherapy

Innate-like T cells (ILTCs) link innate immune responses with adaptive immune functions. This group includes invariant natural killer T (iNKT) cells, mucosa-associated invariant T (MAIT) cells, and γδ T cells. ILTCs detect transformed or stressed cells via non-classical antigen presentation pathways. For example, iNKT cells recognize CD1d-presented glycolipids, MAIT cells respond to MR1-presented metabolites from riboflavin pathways, and γδ T cells sense phosphoantigens through butyrophilin-dependent mechanisms and stress ligands. These features support early tumor control and shape downstream immunity by promoting dendritic cell activation, NK cell function, and priming of tumor-reactive CD8+ T cells. In established tumors, ILTC activity is frequently suppressed. Reduced antigen presentation, inhibitory cytokines, hypoxia, and metabolic constraints, including lactate accumulation and kynurenine production, limit effector responses and promote hyporesponsive states. Transcriptional regulators such as TOX, NR4A family members, and BATF are associated with these programs. This review discusses ILTC roles in tumor surveillance, immune escape, and therapeutic strategies to restore their function.