T cells have the potential to eliminate cancer cells. Immunotherapies that exploit this ability have become a standard of care across different cancers. Emerging evidence indicates that effective and long-lasting antitumor protection is determined by the interplay of circulating and tissue-resident T cells with other immune cells in the tumor microenvironment and lymph nodes. We are comprehensively studying the molecular and cellular networks interplay of circulating and tissue-resident T cell compartments in human cancers using functional assays, multidimensional flow cytometry, single-cell and spatial transcriptomics, and in vivo models. We aim to reveal new insights into these networks that impact cancer progression and harness this knowledge to improve immunotherapies.