Roles of Granulocytic myeloid-derived suppressor cells in regulating NSCLC Malignancy

Jie Jiang¹Mingqiang Zhong¹Jian Wang²Zhiping Deng^1*

• ¹Department of Respiratory and Critical Care Medicine, Zigong First People’s Hospital, Zigong 643000, China, Zigong, China
• ²Department of Oncology, Jiangjin Hospital, School of Medicine, Chongqing University, Chongqing, 402260, PR China, Chongqing, China

Granulocytic myeloid-derived suppressor cells (G-MDSCs) play a pivotal role in immunosuppression, tumor progression, and therapeutic resistance in non-small cell lung cancer (NSCLC). As the predominant subset of myeloid-derived suppressor cells (MDSCs), G-MDSCs impair anti-tumor immunity by suppressing NK cell function through mechanisms involving arginase-1 (Arg-1)– mediated L-arginine depletion, reactive oxygen species (ROS) production, and secretion of immunosuppressive cytokines. Elevated G-MDSC levels correlate with advanced tumor stage, poor prognosis, and diminished efficacy of immune checkpoint inhibitors, highlighting their potential as both a prognostic biomarker and therapeutic target. Emerging strategies to counteract G-MDSC-mediated immunosuppression include inhibition of STAT3 signaling, metabolic reprogramming, blockade of chemokine-mediated recruitment, and induction of differentiation using agents like all-trans retinoic acid (ATRA). Additionally, targeting G-MDSC survival through endoplasmic reticulum (ER) stress modulation or TRAIL-R–mediated apoptosis represents a promising approach. Combinatorial therapies integrating G-MDSC-targeting agents with immune checkpoint blockade or chemotherapy may enhance therapeutic outcomes in NSCLC. This review summarizes current insights into the biology of G-MDSCs, their immunosuppressive mechanisms, and translational strategies to mitigate their pro-tumorigenic effects, providing a roadmap for future research and clinical development in NSCLC immunotherapy.