NIR-Triggered Phase-Change Microspheres for Synergistic Thermal Ablation, Calcium Overload, and Lactate Neutralization Therapy of Tongue Squamous Cell Carcinoma

Abstract Tongue squamous cell carcinoma (TSCC) ranks among the most aggressive malignancies of the head and neck, marked by a highly acidic and immunosuppressive tumor microenvironment (TME) in which lactate accumulation persistently drives tumor-associated macrophages (TAMs) toward M2 polarization, promoting local recurrence. Given the superficial anatomical location and immunosuppressive TME of TSCC, developing local therapeutic strategies that combine spatiotemporal controllability with the capacity to reverse TME immunosuppression is of considerable significance. In this work, we construct near-infrared (NIR)-triggered phase-change core–shell microspheres, CaO-ICG-Cap@LA, consisting of an indocyanine green (ICG) and CaO particle core encapsulated within a lauric acid (LA) phase-change shell in which capsaicin (Cap) is dissolved. Upon 808 nm NIR irradiation, ICG-mediated photothermal heating melts the LA shell (melting point ~ 43°C), triggering the rapid release of capsaicin and CaO. The exposed CaO undergoes an exothermic hydration reaction (CaO + H₂O → Ca(OH)₂ + ΔH), the released heat augments local photothermal ablation; the resulting Ca(OH)₂ neutralizes TME lactate, disrupting lactate-driven M2 polarization and promoting TAM repolarization toward the M1 phenotype; and the liberated Ca²⁺ ions undergo massive influx through capsaicin-activated TRPV1 channels, inducing calcium overload-mediated cell death. In a CAL-27 xenograft model, CaO-ICG-Cap@LA (+ NIR) treatment produced marked tumor suppression, with extensive intratumoral calcium deposition and apoptotic signals, a shift in TAM polarization from M2 toward M1, and no evident pathological damage to major organs. By integrating TRPV1-mediated calcium overload, photothermal ablation enhancement, and lactate neutralization into a single platform, these phase-change microspheres offer a chemotherapy-independent combination strategy for TSCC treatment.