Mechanisms of T cell-mediated antitumor immunity within tertiary lymphoid structures.

Tertiary lymphoid structures (TLS) are ectopic lymphoid-like organs formed under chronic inflammatory stimulation, which have been increasingly recognized as indicators of favorable clinical prognosis and enhanced immunotherapy response in multiple solid tumors. T cells are essential constituents of TLS, involved in their formation, maintenance, and immune function. They exhibit substantial heterogeneity in quantity, phenotype, and spatial localization across different tumor types. Follicular helper T (Tfh) cells act as a central subset in TLS by promoting B cell activation, germinal center (GC) development, and antibody production. They have been widely regarded as key predictors of favorable therapeutic response and prolonged survival. In addition, peripheral helper T (Tph) cells, regulatory T (Treg) cells, and follicular regulatory T (Tfr) cells also perform immunomodulatory functions within TLS. Their effects can either enhance or suppress antitumor responses, depending on the tumor type, TLS spatial distribution, and maturation status. This review examines the phenotypic heterogeneity, functional fate, and intercellular interactions of T cells within TLS. It also explores the immunoregulatory role of TLS and their potential in novel immunotherapy strategies. Further research should aim to the evolution process of immune populations within TLS and standardized model establishment, in order to accelerate their clinical translation in precision immunotherapy.