Enhanced Osteosarcoma Immunotherapy via CaCO₃ Nanoparticles: Remodeling Tumor Acidic and Immune Microenvironment for Photodynamic Therapy

Abstract

Osteosarcoma (OS) is a “cold” tumour enriched in noninflammatory M2 phenotype tumour‐associated macrophages (TAMs), which limits the efficacy of immunotherapy. The acidic tumour microenvironment (TME), generated by factors such as excess hydrogen (H+) ions and high lactate levels, activates immunosuppressive cells (e.g., M2 phenotype TAMs), further promoting a suppressive tumour immune microenvironment (TIME). Therefore, a multitarget synergistic combination strategy that neutralizes the acidic TME and reprograms TAMs can be beneficial for OS therapy. Here, a calcium carbonate (CaCO3)/polydopamine (PDA)‐based nanosystem (A‐NPs@(SHK+Ce6)) was developed for the targeted codelivery of the photosensitizer Ce6 and shikonin (SHK) to OS tumours via the bone‐targeting ability of alendronate sodium (ALN). CaCO3 nanoparticles were used to neutralize H+ ions and alleviate the suppressive TIME, and the loaded SHK not only synergized with photodynamic therapy (PDT) by promoting reactive oxygen species (ROS) generation and enhancing immunogenic cell death (ICD) but also inhibited lactate production, further reversing the acidic TME and repolarizing TAMs to consequently lead to enhanced PDT‐induced tumour suppression and comprehensive beneficial effects on antitumour immune responses, including the promotion of CD8+ T‐cell infiltration and regulatory T‐cell (Treg) suppression. Importantly, A‐NPs@(SHK+Ce6), in combination with programmed cell death protein 1 (PD‐1) checkpoint blockade, showed a remarkable ability to eliminate distant tumours and promote long‐term immune memory function to protect against rechallenged tumours. This work presents a novel multiple‐component combination strategy that coregulates the acidic TME and TAM polarization to reprogram the TIME.This article is protected by copyright. All rights reserved