Nanomaterial‐Mediated Radiotherapy–Immunotherapy Combinations: Breaking Immunosuppression and Revolutionizing Cancer Treatment

ABSTRACT

Malignant tumors remain a leading cause of global mortality. Radiotherapy (RT) and immunotherapy are established cornerstone therapies for most solid cancers. Their combination, radio‐immunotherapy (IRT), has demonstrated robust synergistic antitumor activity in preclinical models and early‐phase clinical trials. However, broader clinical implementation is hindered by intrinsic or acquired radioresistance, systemic toxicities with overlapping organ tropism, and a profoundly immunosuppressive tumor immune microenvironment (TIME). To address these limitations, this review presents a mechanistically integrated framework centered on nanomaterial‐enabled strategies: targeted radiosensitization coupled with enhanced immunogenic cell death (ICD); spatiotemporally controlled remodeling of the TIME to counteract immunosuppression; and multifunctional, imaging‐guided theranostic platforms for precision IRT delivery and response monitoring. We systematically synthesize recent preclinical advances in nanomaterial‐enhanced IRT—including applications across conventional X‐ray, proton beam, photothermal, and sonodynamic irradiation—and critically evaluate early‐phase clinical data for representative nanotherapeutics (NBTXR3 and AGuIX). Furthermore, we identify and analyze key translational bottlenecks impeding clinical adoption, including scalability, regulatory pathway clarity, and biomarker‐driven patient selection. Collectively, this review provides a unified, mechanism‐informed foundation to advance rational nanomaterial design and evidence‐based clinical translation, thereby strengthening the scientific basis for precision oncology in patients with refractory solid tumors.