The efficacy of mild photothermal therapy (mPTT) is severely limited by insufficient immune activation and a highly immunosuppressive tumor microenvironment (TME), often leading to failed suppression of tumor metastasis. To overcome these challenges, we developed CBT, a functional black phosphorus-based nanomedicine that co-delivers calcium ions (Ca2+) and the immunomodulator triptolide (TPL). In the acidic TME, CBT releases Ca2+, and upon 808 nm laser irradiation, the generated mild heat (42–45 °C) not only potentiates the therapy but also facilitates additional extracellular Ca2+ influx. This cascade induces profound intracellular calcium overload. The disrupted ionic homeostasis acts synergistically with TPL to downregulate heat shock protein (HSP) expression, thereby overcoming tumor thermoresistance, enhancing the release of tumor-associated antigens (TAAs), and triggering robust immunogenic cell death (ICD). Concurrently, TPL, as a natural immunomodulator, downregulates programmed death-ligand 1 (PD-L1) on tumor cells to block PD-1/PD-L1-mediated immune escape. Distinct from conventional single-component or simple combined photothermal systems, our CBT features pH/laser dual-responsive sequential drug release, which perfectly coordinates therapeutic procedures. The combination of CBT-enhanced mPTT and TPL-mediated immunoregulation thus achieves potent “heat-potentiated immunotherapy”. In a murine 4T1 bilateral tumor model, this strategy successfully eradicated untreated distant tumors, which was correlated with a significant increase in tumor-infiltrating CD8+ T cells and a reduction in immunosuppressive cells (Tregs and M2-type TAMs). This work highlights the promise of functional black phosphorus nanomedicine in advancing mPTT and broadens the application of traditional Chinese herb-derived agents in modern cancer immunotherapy.
Keywords: Mild photothermal therapy; Calcium overload; Triptolide; Heat shock proteins; Immunotherapy
