Review of radiotherapy combined with immune checkpoint inhibitors for microsatellite stable locally advanced rectal cancer

Abstract Colorectal cancer maintains a significant global health burden, ranking as the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality. For patients with locally advanced rectal cancer (LARC), the cornerstone of treatment has historically involved a multimodal approach combining surgery, chemotherapy (ChT), and radiotherapy (RT). Standard neoadjuvant (preoperative) strategies typically consist of either long-course RT (45–54 Gy delivered in 25–30 fractions) with concurrent fluoropyrimidine-based ChT, or short-course RT alone (25 Gy in 5 fractions). Despite these established protocols, a substantial proportion of patients (10%-30%) still experience disease recurrence and metastasis, highlighting a clear need for therapeutic advancements. Recently, growing mechanistic evidence has elucidated a synergistic antitumor effect between immunotherapy (IT) and RT. This synergy, stemming from RT’s ability to modulate the tumor immune microenvironment and enhance systemic antitumor immunity, positions the combination of RT and IT, termed radioimmunotherapy (RIT), as a promising novel strategy to improve outcomes. This review examines the most promising RIT approaches currently under clinical investigation for LARC and outlines a potential roadmap for the future development of this evolving therapeutic paradigm.