Reversing Photodynamic Therapy‐Induced Tumor Metabolic Symbiosis and Immune Evasion Delivers a Two‐Punch Attack on Tumors

Abstract Photodynamic therapy (PDT) is an attractive approach for tumor treatment because of its precision, potent cytotoxic effect, and low risk of resistance compared to conventional cancer treatments. However, PDT consumes oxygen. The oxygen depletion effects in PDT‐treated tumor cells can elevate lactic acid production and efflux, promoting the progression of surrounding tumor cells through tumor metabolic symbiosis and promoting macrophages to M2‐type polarization for supporting tumor progression. Herein, a multifunctional nanosystem is developed for the intracellular co‐delivery of the photosensitizer (ICG), the nanozyme (iron oxide nanoparticles, MNPs), and siMCT4 (siRNA for monocarboxylate transporter 4). In tumor cells undergoing PDT, siMCT4 inhibits lactate efflux, thereby limiting extracellular lactate‐associated malignancy and immune evasion. Meanwhile, both the reduction of extracellular lactate levels and the presence of MNPs in the tumor microenvironment promote the M1‐type polarization to enhance the antitumor activity of macrophages. Furthermore, the intracellular lactic acid accumulation and M1‐type macrophage‐secreted H ₂ O ₂ facilitate the MNPs‐mediated chemodynamic therapy (CDT). Therefore, the intelligent nanosystem, IM@iPPAE@siMCT4, can regulate the intra/extracellular lactate levels and the M1‐type macrophage polarization to deliver a two‐punch attack on tumor cells. This nanosystem circumvents the problems arising from antitumor PDT.