Abstract: In recent years, substantial advancements have been achieved in tumor immunotherapy by leveraging the host immune system, with particular emphasis on TLR7/8 agonists due to their distinctive immunomodulatory capabilities. As endosomal pattern recognition receptors, TLR7/8 enhance anti-tumor immune responses by activating MyD88-dependent signaling pathways through the recognition of single-stranded RNA or small molecular compounds. This article comprehensively reviews the research progress of combining TLR7/8 agonists with radiotherapy for tumor treatment, with a focus on the clinical translational potential of intratumoral injection strategies. Numerous clinical studies demonstrate that the intratumoral injection of TLR7/8 agonists in combination with radiotherapy can significantly suppress both primary and metastatic lesions by inducing immunogenic cell death, releasing tumor antigens, activating local immune responses, and triggering abscopal effects. Moreover, innovative sustained-release formulations and the development of "endogenous vaccines" have further improved treatment safety and prolonged therapeutic efficacy. Despite challenges such as suppression from the tumor microenvironment and dose optimization, TLR7/8 agonists, when combined with immune checkpoint inhibitors, nano-delivery technologies, and precise biomarker selection, offer promising prospects for establishing a new paradigm in the treatment of cold tumors, thereby advancing tumor immunotherapy from localized control to systemic eradication.