Synergistic strategy based on mild phototherapy and deep tumor hypoxia reversal comprehensively remodels the tumor microenvironment for improved immunotherapy

Immunotherapy has shown remarkable therapeutic efficacy in triple-negative breast cancer (TNBC), but successful immune responses occur in only a subset of patients due to the hostile tumor microenvironment (TME). Specifically, low immunogenicity, dense extracellular matrix, and immunosuppressive environment in the TME are difficult to bypass for immunotherapy. The hypoxic environment of solid tumors not only contributes to an unfavorable TME but also functions in inhibiting the therapeutic effect of multiple antitumor methods, especially photodynamic therapy (PDT). In this study, we successfully developed a synergistic regulation nanosystem with albumin-mediated tumor targeted delivery of the photosensitizer IR780 and oxygen-generating nanoenzyme MnO2. As expected, MnO2 responsively catalyzed the decomposition of endogenous tumor H2O2 into O2, thereby enhancing the effect of PDT in triggering immunogenic cell death (ICD) and boosting tumor immunogenicity. Additionally, the enhanced PDT also functions in eliminating the tumor stromal barrier, facilitating the infiltration of effector T cells and therapeutics. The subsequent delivery of nanosystems containing MnO2 could reach deeper into the core of the tumor to alleviate severe hypoxia. Furthermore, relief of deep tumor hypoxia could significantly induce vascular normalization and reversal of tumor immunosuppression, decreasing the negative immunomodulatory cells such as Tregs and MDSCs. Resultantly, a positive feedback loop between mild phototherapy and deep hypoxia reversal was established using the synergistic strategy, which achieved comprehensive TME remodeling. Its combination with PD-L1 checkpoint blockades could lead to the regression of primary tumors and untreated metastasis tumors by inducing a strong systemic immune response, enhancing the immunotherapeutic efficacy for TNBC.