Engineering the tumor immune landscape: Translating non-invasive physical stimulation into tumor-associated...

Tumor-associated macrophages (TAMs) shape the tumor microenvironment through plastic transitions between pro-inflammatory M1-like and immunosuppressive M2-like states, yet clinical drug therapies are limited by toxicity, resistance, and delivery barriers. This review explains how non-invasive physical stimulation (NIPS) reprograms TAMs via defined couplings between physical inputs and signaling pathways. Hypoxia-tolerant photodynamic strategies and mild photothermal heating reset hypoxia- and lactate-driven programs; cavitation-dominant ultrasound and sonodynamic therapy trigger danger signaling and reactive oxygen species; ultrasound microbubble destruction provides endothelial repair cues; nanosecond pulsed electric fields activate cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway; piezoelectric materials convert mechanical input into calcium-dependent transcription; and appropriately dosed radiotherapy elicits immune-active responses while avoiding hypoxia-driven M2 recruitment. Across models, these regimens promote pro-inflammatory reprogramming, normalize aberrant vasculature, and strengthen antitumor immunity while restraining immunosuppression. We synthesize parameter windows, delivery options, and combination strategies with checkpoint blockade and macrophage-directed agents to guide the translation of NIPS into precise, low-toxicity TAM-targeted immunotherapy.