Clonotype-resolved T-cell response monitoring via repertoire-wide multidimensional TCR decoding

T cell responses across the TCR repertoire are central to immunotherapies. However, current methods cannot simultaneously achieve broad antigen coverage, high TCR resolution, and high throughput, and therefore provide only a partial view of T cell responses. Here, we introduce the T-SCOPE strategy for repertoire-wide, clonotype-resolved T cell response monitoring. By directly linking response potency with TCR sequences across the entire TCR repertoire, T-SCOPE facilitates the unbiased identification and assessment of antigen response potency for individual TCRs. T-SCOPE integrates single-cell RNA sequencing, paired single-cell TCR sequencing, and cell-surface DNA barcoding to simultaneously profile gene expression, labeling intensity, sample identity, and TCR sequences at single-cell resolution. This platform enables response potency ranking of antigen-specific TCRs and monitors the T cell response landscape to global tumor antigens in human clinical samples. Altogether, T-SCOPE provides a functional platform for monitoring dynamic antigen responses in both physiological and clinical settings.