Self-promoted tumor-targeting nanomedicine activates STING-driven antitumor immunity via photodynamic DNA damage and PARP inhibition

The activation of antitumor immunity through strategically designed nanomedicine presents a promising approach to overcome the limitations of conventional cancer therapies. In this work, bioinformatic analysis found an abnormal poly(ADP-ribose) polymerase-1 (PARP-1) expression in breast cancer, linked to the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) pathway and immune suppression. PARP-1 inhibitor screening revealed olaparib (Ola) as a promising candidate, enhancing DNA damage and potentiating the immunotherapeutic response. Consequently, a self-promoted tumor-targeting nanomedicine (designated as PN-Ola) was proposed to activate STING-driven antitumor immunity through photodynamic DNA damage and PARP inhibition. PN-Ola was composed of a programmed death-ligand 1 (PD-L1) targeting amphiphilic peptide-photosensitizer conjugate (C₁₆-K(PpIX)-WHRSYYTWNLNT), which effectively encapsulates Ola. Notably, PN-Ola demonstrated selective accumulation in tumor cells that overexpress PD-L1, while concurrently enhancing PD-L1 expression, thereby establishing a self-promoting mechanism for improved drug accumulation within tumor cells. Meanwhile, the photodynamic therapy (PDT) effects of PN-Ola would result in oxidative DNA damage and subsequent accumulation of DNA fragments. Additionally, the PARP inhibition provided by PN-Ola disrupted the DNA repair pathways in tumor cells, leading to a boosted release of DNA fragments that further stimulated STING-driven antitumor immunity. The synergistic mechanism of PN-Ola effectively activates the immunotherapeutic response by enhancing T cell activation and infiltration, leading to the eradication of metastatic tumors without inducing side effects. This study presents a promising strategy to overcome targeting ligand heterogeneity while activating systemic antitumor immunity for the effective eradication of metastatic tumors.