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

Xuan Zhang,Jinwei Bai,Shihao Sun,Yu Li,Xinxin Li,Genping Meng,Wenyuan Cheng,Yuhui Yin,Zhiyi Wang,Baodui Wang

Published 2025 in Biomaterials

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.

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