Chiral nanoassembly remodels tumor microenvironment through non-oxygen-dependent depletion lactate for effective photodynamic immunotherapy

Abstract

Targeting lactate metabolism in tumor microenvironment (TME) has emerged as a promising strategy for enhancing immunotherapy. However, the commonly used strategy of lactate oxidation by lactate oxidase consumes oxygen, exacerbating tumor hypoxia and hindering immunotherapy. Here, we present a novel tumor-targeting, near infrared light-activated and TME-responsive chiral nanoassembly (Zn-UCMB) for enhancing photodynamic triggered immunogenic cell death (ICD) through a nonoxygen-dependent depletion of lactate. In the moderately acidic TME, the chiral Zn complex liberated from the Zn-UCMB selectively coordinates with l-lactate, leading to the depletion of lactate. Additionally, the Zn-UCMB facilitates the decomposition of H₂O₂ into O₂, which significantly enhances the efficacy of photodynamic therapy (PDT) and triggers a robust ICD effect. Moreover, the nonoxygen-dependent depletion of lactate can reprogram the TME by reducing the expression of HIF-1α, decreasing VEGF expression, and mitigating immunosuppressive conditions. This prompts the phenotypic transformation of tumor-associated macrophages from M2 to M1. Consequently, Zn-UCMB not only enhances the efficacy of PDT but also elicits a potent ICD during 980 nm laser irradiation, thereby effectively suppressing tumor growth and metastasis. The findings offer a novel approach to overcome the limitations of existing lactate metabolism-targeting strategies and provide a promising therapeutic option for enhancing the efficacy of immunotherapy.

Keywords: Cancer immunotherapy; Chiral nanoassembly mediated immunogenic cell death; Nonoxygen-dependent depletion of lactate; Photodynamic therapy; Tumor microenvironment modulation.