3029 - Targeting Tumor Cell MALT1 Reprograms Tumor Microenvironment via Macrophage M1 Polarization and Overcomes Radioresistance in NSCLC
Presenter(s)
S. Bao1, F. Wang2, C. Tian2, J. Ma2, H. Yang2, J. Liu2, J. Wang2, Y. Wang, M. Wu4, J. Yu4,5, and D. Chen2,6; 1Shandong University Cancer Center, Shandong University, Jinan, China, 2Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 3Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China, 4Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China, 5Department of Radiation Oncology and Shandong Provincial Key Laboratory of Precision Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China
Purpose/Objective(s):
Previous studies have demonstrated that Mucosa-associated lymphoid tissue translocation gene 1 (MALT1) inhibitors synergize with immunotherapy to enhance antitumor efficacy. However, the impact of MALT1 inhibition on radiotherapy efficacy remains unknown. This study aims to investigate the potential of MALT1 as a prognostic biomarker in radiotherapy-treated patients and to elucidate its underlying mechanisms in remodeling the immune microenvironment and overcoming radioresistance in non-small cell lung cancer (NSCLC).Materials/Methods:
A retrospective cohort analysis was performed on tissue specimens from NSCLC patients undergoing curative radiotherapy. The expression of MALT1 in radiosensitive and radioresistance NSCLC tissues were validated by immunohistochemistry. Murine xenograft models were established and administered either the MALT1-specific inhibitor Mepazine or shRNA-mediated knockdown combined with localized radiotherapy. Flow cytometry was used to assess the infiltration and the function of immune cells. Integrated transcriptomic and proteomic analyses revealed that MALT1 differentially regulates CD73 expression. Compartment-specific adenosine quantification was subsequently performed, with tumor cell-intrinsic adenosine levels measured by real-time quantitative PCR (RT-PCR) and stromal adenosine concentrations determined via enzyme-linked immunosorbent assay (ELISA). Additionally, tumor cells and macrophages co-culture experiments were implemented to validate tumor cell-mediated regulation of macrophage polarization.Results:
Elevated MALT1 expression correlates with diminished survival outcomes and reduced immune infiltration in radiotherapy-treated NSCLC patients. In tumor-bearing murine models, pharmacological inhibition or gene silencing of MALT1 synergized with radiotherapy to potentiate antitumor effects and improve survival. Flow cytometry demonstrated that combined MALT1 inhibition and radiotherapy preferentially augmented M1-polarized macrophage infiltration while elevating the M1/M2 macrophage ratio in the tumor microenvironment. Mechanistic investigations revealed that dual therapy downregulated CD73 expression, consequently suppressing adenosine accumulation in the tumor microenvironment. Adenosine depletion facilitated macrophage M1 polarization, thereby amplifying radiation-induced antitumor immunity.Conclusion:
Our study establishes that combining radiotherapy with MALT1 inhibitors suppresses the CD73-adenosine axis and promotes M1 macrophage polarization, thereby reprogramming the tumor microenvironment. These findings identify MALT1 as a clinically significant prognostic biomarker for NSCLC patients undergoing radiotherapy and demonstrate that therapeutic targeting of MALT1 synergistically enhances radiation efficacy through microenvironmental immune modulation.