Presenter(s)
X. Xing1,2, R. Xiao1, M. Wu3, J. Yu4, and D. Chen4; 1Shandong Cancer Hospital and Institute, Jinan, shandong, China, 2Shandong University Cancer Center, Shandong University, Jinan, shandong, China, 3Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 4Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
Purpose/Objective(s):
Radiotherapy (RT) can enhance antitumor immunity via MHC-I upregulation, radiotherapy combined with immunotherapy has demonstrated significant efficacy in multiple solid tumors. However, the complex tumor microenvironment frequently induces immune suppression, thereby yielding Radioresistance. SUMOylation is a key stress response, yet its role in post-RT immune modulation is unclear. Here, we aim to investigate the clinical significance and mechanistic role of RT-induced SUMOylation in suppressing MHC-I antigen presentation, whilst exploring the potential of targeting SUMOylation to enhance the efficacy of radiotherapy combined with immunotherapy.Materials/Methods: Tumor tissue samples from clinical radiotherapy patients were collected to analyze the correlation between key SUMOylation genes (SUMO1, SUMO2/3) expression and prognosis. SUMOylation proteomic profiling of paired tumor cells before and after radiotherapy was performed to screen key regulatory molecules. Immunoblotting, Co-IP, and gain/loss-of-function experiments were used to verify the modification pattern of UBC9 and its enzymatic activity changes. Global SUMOylation was inhibited by TAK981, and transcriptome sequencing was employed to analyze alterations in antigen presentation-related pathways
Results:
Clinical data revealed that high expression of SUMO1 and SUMO2/3 in tumors was significantly associated with poor overall survival in radiotherapy patients (P<0.05). Proteomic profiling demonstrated that while UBC9 protein levels remained unchanged, its SUMOylation at the K48 site was markedly upregulated post-radiotherapy, ranking 6th among all upregulated modified genes in terms of fold change. Functional validation confirmed that enhanced K48 modification significantly increased UBC9 enzymatic activity, thereby elevating global SUMOylation levels. Inhibition of global SUMOylation by TAK981 significantly upregulated the antigen processing and presentation pathway; knockdown of UBC9 markedly enhanced transcription of core MHCI signaling molecules TAP1/TAP2. Further Co-IP experiments demonstrated that increased UBC9 modification promoted its interaction with the key transcription factor STAT1, restricting STAT1 nuclear translocation and thereby inhibiting TAP1/TAP2 transcription. In vivo experiments demonstrate that TAK981 combined with RT significantly inhibits the growth of multiple tumor types.Conclusion:
Radiation-induced elevation of global SUMOylation restricts the upregulation of the MHCI antigen presentation pathway via UBC9 K48 modification-mediated impairment of STAT1 nuclear translocation, ultimately contributing to radioresistance. Targeted inhibition of SUMOylation by TAK981 significantly enhances radiation-induced membrane presentation of tumor antigens, providing novel mechanistic insights and translational potential for radiotherapy combined with immunotherapy