BACKGROUND: Bladder intracavitary hyperthermic perfusion chemotherapy (HIPEC) is a promising treatment for non-muscular invasive bladder cancer (NMIBC). However, the molecular mechanisms underlying the response to HIPEC remain poorly understood. This study aimed to elucidate the transcriptomic profiles associated with the response to HIPEC in NMIBC patients. METHODS: RNA sequencing was performed on bladder tumor samples from NMIBC patients who underwent HIPEC treatment. Differentially expressed genes (DEGs) between responders and non-responders to HIPEC were identified. Gene ontology and pathway analysis were conducted to explore the biological functions and pathways enriched in the DEGs. Additionally, the expression of specific immune-related genes was evaluated for their association with HIPEC response. The diagnostic efficiency of selected genes in predicting relapse before and after HIPEC treatment was assessed in a validation cohort. RESULTS: We assessed the expression status of differentially expressed genes (DEGs) between responders and non-responders to HIPEC. Gene ontology and pathway analysis revealed that DEGs were enriched in immune-related pathways, including cytokine-cytokine receptor interaction, chemokine signaling pathway, and antigen processing and presentation. Furthermore, the expression of several immune-related genes, including ZMAP4, UPP2, and GALR1, was significantly associated with the response to HIPEC. Therefore, the immune system's reaction plays a crucial role in the response to HIPEC in patients with NMIBC. At last, a considerable diagnostic efficiency that tissue TMEFF2, KRT222, and GTSF1 in predicting relapse in NMIBC patients after HIPEC treatment, and ZMAP4, UPP2, and GALR1 in predicting relapse in NMIBC patients before HIPEC treatment in the validation cohort. CONCLUSION: Transcriptomic profiling revealed that immune-related pathways and genes play a crucial role in the response to HIPEC in NMIBC patients. These findings suggest that transcriptomic profiling could provide a valuable tool for predicting treatment outcomes and identifying therapeutic targets for NMIBC.