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Bacillus Calmette-Guérin (BCG) is the mainstay of treatment for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC), yet recurrence rates remain high. To improve the efficacy of BCG, a better understanding of the immune landscape underlying BCG resistance is critical. Here, we performed single-cell RNA-sequencing (scRNA-seq) and whole-exome sequencing on tumors from NMIBC patients before and after BCG treatment. Our analysis revealed a marked increase in CD6/ALCAM interactions between T cells and urothelial cells in BCG recurrent tumors. CD6-high T cells were enriched in recurrent tumors and exhibited downregulation of activation-related genes, indicative of functional impairment. These observations were supported by analysis of an independent BCG-treated NMIBC cohort, in which CD6/ALCAM signaling was correlated with shorter recurrence-free survival (p = 0.00059). Our findings reveal a previously unrecognized association between CD6/ALCAM signaling and BCG resistance in NMIBC patients and highlight this pathway as a potential therapeutic target to enhance response to BCG.