Combined Immune‐Peptide Nanofiber with HSP70/AKT/mTOR Axis Blockade Enhances Photothermal Immunotherapy, Inhibiting Tumor Growth and Recurrence

Although immune checkpoint blockade (ICB) therapies have shown clinical benefit, ICBs exert limited effects on most “immune‐cold” solid tumors, i.e., tumors with low immune infiltration. Photothermal immunotherapy (PTIT) converts “cold” tumors into “hot” tumors, thereby enhancing immune responses and improving ICB efficacy. Hence, developing a strategy that can integrate PTIT and ICB treatment is desirable. In this study, we designed a unique carrier‐free PSP@IR‐CF 3 nanofiber, self‐assembled from the programmed death‐ligand 1 (PD‐L1) targeting immune‐peptide NTGYFYGDQ (PSP) and a PTIT agent (IR‐CF 3 ). The nanofibers enable precise tumor targeting and immune checkpoint inhibition by specifically binding to PD‐L1 on the tumor cell surface, also providing an NIR‐mediated photothermal effect. Combining PSP@IR‐CF 3 nanofibers with NIR induced mild PTIT, which effectively activated the tumor immune microenvironment and suppressed tumor growth with lower immunotoxicity. Additionally, we identified activation of the heat shock protein 70 (HSP70) /AKT/mTOR axis following PTIT, suggesting a potential role in post‐treatment tumor survival and recurrence. By incorporating the mTOR inhibitor rapamycin, the combination treatment further enhanced therapeutic efficacy and reduced tumor recurrence.