Synergizing radiotherapy and immunotherapy for locally advanced gastric cancer: evolving paradigms and future directions.

This article innovatively reviews and unveils the synergistic mechanisms, clinical research directions, and future challenges of the combination of preoperative radiotherapy (RT) and immunotherapy (especially the most popular belonging to immune checkpoint inhibitors, ICIs) in the treatment of locally advanced gastric cancer and gastroesophageal junction adenocarcinoma (GC/GEA). The integration of RT and ICIs represents a promising therapeutic strategy for locally advanced, even unresectable, GC/GEA. RT potentiates antitumor immunity by inducing immunogenic cell death (ICD) and targeting iron death, activating the cyclic Guanosine Monophosphate (GMP) and Adenosine Monophosphate (AMP) synthase-stimulator of interferon genes (STING protein) (cGAS-STING) signaling pathway, enhancing the expression level of the major histocompatibility complex (MHC) molecule and immune checkpoint proteins on tumor cells, and promoting immune cell infiltration into the tumor micro-environment. Trials with small sample sizes, such as Neo-PLANET and SHARED, have demonstrated that neoadjuvant chemoradiotherapy (NCRT) combined with ICIs yields encouraging pathological complete response (pCR, ranging from 22.6% to 38.2%) and high R0 resection rates with manageable toxicity profiles. Nevertheless, conflicting results from phase I-II trials like ECOG-ACRIN EA2174 underscore the necessity for patient stratification based on robust biomarkers. Current evidence regarding tumor cell programmed cell death protein ligand 1 (PD-L1) expression (namely, PD-L1 combined positive score or tumor proportion score), tumor mutational burden (TMB), and intratumoral immune micro-environment features for identifying responders still remains inconclusive. Future efforts should prioritize the validation of predictive biomarkers (containing the cutting-edge ctDNA), RT dose, and target area definition (especially for primary positive tumors and high-risk lymphatic drainage); optimization of RT-ICIs sequencing; and the conduct of large-scale randomized controlled trials to establish survival benefits and standardize combination protocols according to the stratified population.