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Here, we develop PRECISE-seq, a method that integrates multi-omics T cell analysis with contact-dependent proximity labeling for rapid screening of disease-relevant T cell repertoires, and for linking the relative TCR avidity with T cell phenotypes at single-cell resolution. PRECISE-seq accurately retrieves CMV-specific clonotypes from human peripheral blood and quantitatively measures functional avidity in physiological contexts. We find that high-potency CMV-specific T cells preferentially acquire an exhausted phenotype. In tumors, polyclonal tumor-reactive CD8+ T cells predominantly differentiate into a protumor Ly49+ regulatory state (TLy49), characterized by inhibitory killer cell lectin-like receptor expression and originating from effector memory T cells along a trajectory distinct from exhaustion. Notably, PD-1 blockade reduces TLy49 formation and promotes effector revival, which correlates with responsiveness to immunotherapy. 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