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.