Across cancers, tumor-infiltrating CD8+ T cells expressing the tissue-resident memory T cell (TRM) markers CD69 and CD103 are strongly associated with favorable clinical outcomes. However, a substantial fraction of these cells in human tumors are not tumor-specific, but instead recognize unrelated viral antigens. These virus-specific bystander TRM-like cells are prevalent in tumors and retain functional potential, raising interest in strategies that leverage pre-existing antiviral immunity for cancer immunotherapy. Yet their origins and differentiation states remain poorly defined, limiting both the interpretation of residency-based tumor-infiltrating lymphocyte (TIL) phenotyping and efforts to rationally harness these TRM-like cells. Here, using mouse models of GBM and melanoma, we demonstrate that resting circulating memory T cells trafficked into tumors via GPCR-dependent signaling and rapidly adopted a tissue-resident phenotype, independent of cognate antigen. Strikingly, in GBM, but not melanoma, pre-existing brain TRM contributed substantially to the bystander TIL compartment and were the dominant source of CD69+/CD103+ bystander T cells, revealing a tumor- and tissue-specific origin for this subset. These findings were further supported by transcriptional analysis of T cell receptor clones present in both paired patient GBM tumor and peritumoral brain, which identified shared features with TRM-derived TILs in mouse GBM. Overall, this work provides new insight into tumor immunosurveillance, inform the interpretation of CD69+/CD103- and CD103+ TIL populations, and lay a foundation for immunotherapeutic strategies aimed at harnessing circulating and pre-existing virus-specific TRM populations in tumors.
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