Slc7a5 promotes T cell anti-tumor immunity through sustaining cytotoxic T lymphocyte effector function. (2025)

Tryptophan (Trp) metabolites have emerged as key regulators of host tumor immunity and cancer patient response to immunotherapy. However, the function of and mechanism underlying Trp in tumor-activated CTLs in the tumor microenvironment are incompletely understood. Using a defined co-culture system of tumor-specific CTLs and cognate antigen-expressing tumor cells, we performed a genome-wide metabolomics screening and observed that Trp level is elevated in the tumor cell-activated CTLs. Parallel genome-wide RNA-Sequencing and ATAC-Sequencing analysis determined that tumor-specific CTLs respond to tumor cells by transcriptionally activating Slc7a5 expression. Pharmacological inhibition of Slc7a5 decreased Trp uptake in tumor-activated CTLs and suppressed CTL lytic activity in killing tumor c