Photoimmunotherapy has been a promising method for eradicating malignant tumors, but remains largely limited by tumor hypoxia and off-target adverse effects. To address these limitations, we develop hypoxia-tolerant small ligand-caged photosensitizer (PS) P1/P2 that are delivered to tumor based on an albumin-hijacking strategy by exploiting endogenous serum albumin as a tumor-localized carrier, achieving exceptional tumor accumulation and overcoming tumor hypoxia to realize the combined photoimmunotherapy. Albumin can trigger the acetyl group of P1/P2, initiating a 1,6-rearrangement elimination cascade to release a quinone methide intermediate captured by albumin to form a stable adduct via site-specific 1,6-Michael addition, as verified by in vitro experiments, including high performance liquid chromatography, mass spectra, spectroscopic spectra, and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analyses but control probes P3/P4 fail. In vivo imaging revealed that P1/P2 displayed more enhanced tumor accumulation post injection than P3/P4 did in 4T1-bearing mouse models and P1 further enabled broad-spectrum efficacy across several tumor models. Moreover, by light-irradiation-generating superoxide anions and hydroxyl radicals, P1-mediated photodynamic therapy achieves tumor-inhibiting action with approximately 92% regression in a breast mouse model and triggers immunogenic cell death induction, synergizing with programmed death-ligand 1 therapy to further activate systemic antitumor immunity and suppress both primary and distant tumors with approximately 95% tumor growth inhibition. Crucially, this platform may extend its applicability to diverse payloads such as imaging agents, therapeutics, and immunomodulators by replacing the PS warhead and advance delivery methods for clinical imaging and therapy.
Wu et al. (Thu,) studied this question.