Functional subsets of tumor-specific CD8⁺ T cells in draining lymph nodes and tumor microenvironment

Accumulating evidence demonstrates that tumor-specific CD8⁺ T cells in tumor-draining lymph nodes (TdLNs) act as an upstream reservoir of exhausted subsets within tumor microenvironment (TME). This reservoir primarily consists of progenitor exhausted CD8⁺ T (T_PEX) cells and newly defined tumor-specific memory subsets (T_TSM). We propose that these two subsets work together to mediate the antitumor effects of PD-1/PD-L1 immune checkpoint blockade (ICB) in a spatiotemporal manner. Although PD-1/PD-L1 ICB monotherapy drives the proliferation and further differentiation of these subsets, it does not alter the programmed differentiation trajectory from T_TSM cells to T_PEX cells, ultimately leading to the development of terminally exhausted CD8⁺ T cells. This phenomenon may partly explaining the frequent relapse in patients following initial ICB therapy. In this review, we focus on the phenotypic and functional heterogeneity of tumor-specific CD8⁺ T cells in both TdLNs and the TME and discuss the implications of these studies for ICB. Our insights aim to illuminate new strategies for advancing tumor immunotherapies.