Combined immune-peptide nanofiber with HSP70/AKT/mTOR axis blockade enhances near-infrared photoimmunotherapy, inhibiting tumor growth and recurrence

Although immune checkpoint blockade (ICB) therapies have shown clinical benefit, ICB remains limited effect on most “immune-cold” solid tumors, i.e., tumors with low immune infiltration. Near-infrared photoimmunotherapy (NIR-PIT) converts “cold” tumors into “hot” tumors, thereby enhancing immune responses and improving ICB efficacy. Hence, developing a strategy that can integrate NIR-PIT and ICB treatment is desirable. In this study, we designed a unique carrier-free PSP@IR-CF ₃ nanofiber (NF), self-assembled from the PD-L1 targeting immune-peptide NTGYFYGDQ (PSP) and NIR-PIT agents (IR-CF ₃ ). The NFs 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. Applying PSP@IR-CF ₃ NFs with NIR induced mild NIR-PIT, which effectively activated the tumor immune microenvironment and treat tumors with lower immunotoxicity. Moreover, we identified that the HSP70/AKT/mTOR signaling pathway, which regulates tumor resistance and recurrence, was activated after PIT. By incorporating mTOR inhibitors like rapamycin, the combination treatment can reduce tumor resistance to NIR-PIT and decrease recurrence, thereby significantly improving therapeutic outcomes. This innovative combination therapy has the potential to revolutionize “cold” tumor treatment by offering more precise interventions that markedly enhance immunotherapeutic efficacy, reduce toxicity, and improve patient outcomes.