The central role of radiotherapy in remodeling the tumor immune microenvironment: mechanisms and therapeutic implications

Radiotherapy is an essential component of multidisciplinary cancer treatment. Its role has expanded from conventional local tumor eradication to active regulation of the tumor immune microenvironment. In recent years, emerging radiotherapy strategies, including FLASH radiotherapy, boron neutron capture therapy, lattice radiotherapy, spatially fractionated radiation therapy, precision particle therapy, immunomodulatory stereotactic body radiotherapy, and immune-optimized carbon ion therapy, have provided new opportunities to improve tumor control, reduce normal tissue toxicity, and overcome radioresistance. Radiotherapy can induce DNA damage and immunogenic cell death, promote tumor antigen release, enhance dendritic cell maturation and antigen cross-presentation, and increase CD8 + T-cell infiltration and antitumor immunity through the cGAS-STING type I interferon pathway. However, radiotherapy may also trigger immunosuppressive feedback, including the accumulation of myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells, as well as the upregulation of immune checkpoint molecules such as programmed death-ligand 1 (PD-L1). These changes may limit antitumor immune responses and contribute to radioresistance. Combining radiotherapy with immune checkpoint inhibitors can amplify antitumor immunity, but therapeutic efficacy is influenced by dose fractionation, treatment timing, tumor type, and baseline immune status. This mini review summarizes emerging radiotherapy strategies and their regulatory effects on the tumor immune microenvironment, and discusses the mechanistic basis, current challenges, and future directions of radiotherapy combined with immunotherapy.