Cysteine-Inspired Photosensitizer with Efficient Tumor Accumulation Enables Thermoresistance Reversal for Reciprocal Enhancement of Photodynamic–Photothermal Therapy

Abstract Insufficient tumor accumulation and heat shock protein (HSP)-mediated adaptive resistance remain major barriers to effective cancer therapy. Here, a cysteine-inspired conjugated polymer photosensitizer (CP-PCys) was developed to integrate enhanced tumor accumulation, hydrogen sulfide (H2S) generation, photodynamic therapy (PDT), and photothermal therapy (PTT). Dense cysteine functionalization promoted cellular uptake, resulting in approximately 2.4-fold higher accumulation in 4T1 cells than that of the polyethylene glycol-functionalized control after 24 h. Meanwhile, the conjugated backbone enabled NIR-II fluorescence imaging, a photothermal conversion efficiency of 52.3%, and efficient reactive oxygen species generation (58.6%). Intracellular H2S disrupted energy metabolism and suppressed HSP70 expression, while PDT-generated reactive oxygen species further reinforced this effect. Combined irradiation reduced HSP70 expression to approximately 57% of the PBS control level, thereby sensitizing tumor cells to PTT. Conversely, PTT-induced hyperthermia enhanced reactive oxygen species generation and potentiated PDT, aggravating mitochondrial dysfunction and DNA damage. In 4T1 tumor-bearing mice, CP-PCys rapidly accumulated in tumors and produced stable mild photothermal heating. Combined PDT–PTT achieved an 89% tumor inhibition rate without detectable skin injury or systemic toxicity, demonstrating the potential of CP-PCys for effective and atraumatic cancer phototherapy.