Engineering the tumor immune landscape: Translating non‐invasive physical stimulation into tumor‐associated macrophage‐targeted cancer immunotherapy

Abstract 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.