Abstract
Immunotherapy has become a promising and transformative approach for treating advanced or treatment-resistant bladder cancer (BCa). However, its efficacy remains limited due to the immunosuppressive tumor microenvironment (TME) and insufficient immune cell infiltration. Photothermal therapy (PTT), which could cause immunogenic cell death (ICD) in tumor tissue, has been explored as a synergistic approach for bladder cancer immunotherapy. Yet, thermal resistance in cancer cells often undermines the effectiveness of PTT. To address these challenges, we proposed a novel strategy that combines PTT with cuproptosis, a recently identified form of ICD, by engineering Tim-3-overexpressing T cell membrane-coated nanoparticles (Tim3@PHSM@IC) to enhance BCa immunotherapy. The overexpression of Tim-3 on the T cell membrane enabled precise targeting of tumor cells and competitively inhibited the Tim-3 receptor on T cells through recognition of Galectin-9. In vitro, Tim3@PHSM@IC nanoparticles effectively induced photothermal cytotoxicity and robust cuproptosis. In vivo, these nanoparticles significantly inhibited tumor growth in multiple BCa mouse models. Flow cytometry (FCM) and RNA sequencing (RNA-seq) analyses revealed that Tim3@PHSM@IC nanoparticles reprogrammed the TME by activating immune-related genes and enhancing ICD This study highlights the potential of Tim3@PHSM@IC nanoparticles in overcoming the immunosuppressive TME and improving the efficacy of BCa immunotherapy by integrating PTT and cuproptosis.