Resistance to radiotherapy (RT) presents a significant clinical challenge in management of cancer. Recent evidence points to specific mechanisms of resistance within the tumor microenvironment (TME), which we aim to discuss, with the aim of overcoming the clinical challenge.We performed the narrative review using PubMed and Web of Science databases to identify studies that reported the regulative network and treatments of RT resistance from TME perspectives.RT significantly changes the immune TME of cancers, which is closely appearing to play a key role in RT resistance (RTR) by modulating immune cell infiltration and function. Various phenotypes are involved in the development of RTR, such as autophagy, senescence, oxidative stress, cell polarization, ceramide metabolism, and angiogenesis in the TME. Key genes and pathways are also implicated in RTR, including immune and inflammatory cytokines, TGF-β, P53, the NF-κB pathway, the cGAS/STING pathway, the ERK and AKT pathway, and the STAT pathway. Based on the mechanism of RTR in the TME, many proposed routes to overcome RTR, several specifically target the TME including targeting fibroblast activation protein, exosomes management, nanomedicine, and immunotherapy. Many challenges in RT resistance still need to be further explored with emerging investigative methods, such as artificial intelligence, genetic technologies, and bioengineering.The complex interactions between RT and TME significantly affect the efficiency of RT. Novel approaches to overcome this clinical difficulty are promising, which needs future work to further explore and identify better treatment strategies.Copyright © 2025 Elsevier B.V. All rights reserved.