Photothermal therapy (PTT) may lead to healthy tissue damage, tumor metastasis, and recurrence, which makes mild photothermal therapy (mild PTT) stand out. However, overcoming heat resistance, insufficient therapeutic effect, and poor photothermal conversion efficiency has become new challenge. Herein, we report a dynamic supramolecular nanocarrier formed from amide-sericin and aldehyde-polyhydroxy glucan (denoted as SDA), the loose cavity of which can be filled by using the pharmaceutical combination of lonidamine (LND) and NIR-II photothermal agent of IR-1061, producing SDLI with a tighter inner hole, smaller and uniform particle size and excellent stability due to multiple pulling forces. Moreover, the intricate internal network structure prevents the hydrophobic IR-1061 from forming aggregates in the small cavity, and the photothermal conversion efficiency (PCE) can reach 48.9%. At the acidic tumor microenvironment of pH 6.5, the controlled release of LND can solve the problem of heat resistance of NIR-II mild PTT and significantly improve the therapeutic effect of NIR-II mild PTT. Meanwhile, SDLI also shows a reasonable tumor inhibition rate, so the synergistic strategy of inhibiting tumor energy metabolism and NIR-II mild PTT to magnify mitochondrial oxidative stress, continuous cell stress state-induced immunogenic cell death to promote the induction of tumor apoptosis is proposed to achieve more effective cancer treatment.

Despite immunotherapy involving immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy, the clinical efficacy is limited due to ICI resistance. Pyroptosis is a gasdermin-mediated programmed cell death that enhances responses to ICIs. However, nontargeted elicitation of pyroptosis may induce systemic side effects and toxicity. Therefore, we reasonably design and construct a tumor-specific prodrug that combines the heat shock protein 90 inhibitor tanespimycin (17-AAG) with the photosensitizer chlorin e6 (Ce6) to induce pyroptosis, by utilizing the high glutathione level in the tumor microenvironment. The released Ce6 and 17-AAG produce reactive oxygen species by laser triggering, which induces gasdermin E-mediated pyroptosis. Furthermore, 17-AAG reduces myeloid-derived suppressor cells and sensitizes tumors to anti-programmed death-1 (PD-1) therapy. Thus, our prodrug strategy achieves tumor-targeted pyroptosis to suppress tumor growth, thereby improving the response to anti-PD-1 therapy and extending the survival of 4T1 breast tumor-bearing mice. Consequently, this pyroptosis-based prodrug represents a novel strategy for enforcing immunogenic photodynamic therapy.