HDACs-targeting photosensitizer-based local-therapy augmenting photoimmunotherapy in bladder cancer

Immune checkpoint inhibitors (ICIs) represent a promising therapeutic strategy in bladder cancer (BCa), while limited response rates as monotherapy significantly restrict clinical application. To address this, we prepared QTANHOH, a quinoxalinone-based photosensitizer with histone deacetylases (HDACs)-targeting capability, for photoimmunotherapy in BCa. QTANHOH exhibited great phototoxicity under both normoxic and hypoxic conditions, alongside excellent bioavailability and high tumor specificity in BCa models. QTANHOH-mediated photodynamic therapy (PDT) effectively induced immunogenic cell death (ICD) in BCa cells and modulated the tumor microenvironment through localized treatment, enhancing therapeutic efficacy. Furthermore, combining QTANHOH-mediated PDT with immune checkpoint inhibitors (ICIs) synergistically improved photoimmunotherapy outcomes in BCa. This combination approach represents a promising strategy for augmenting immunotherapeutic responses in BCa through molecular-targeting photosensitizer.