TIPE2 regulates LRRC33-Mediated TGF-β1 activation in MDSCs to restrict lung cancer PD-1 blockade immunotherapy.

Lung cancer remains a leading cause of cancer-related mortality, with immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 antibodies offering limited clinical benefits due to primary or adaptive resistance. Myeloid-derived suppressor cells (MDSCs) contribute significantly to this immunosuppressive tumor microenvironment (TME), partly through transforming growth factor-β1 (TGF-β1) activation. TGF-β1 is anchored and presented on the MDSC surface via leucine-rich repeat-containing protein 33 (LRRC33), but the intracellular regulatory mechanisms controlling this process are poorly understood. This study investigates the role of tumor necrosis factor-α-induced protein 8-like 2 (TIPE2) in regulating LRRC33-mediated TGF-β1 activation in MDSCs. Using in vitro MDSC cultures and an in vivo Lewis lung carcinoma (LLC) mouse model, along with techniques including Western blot, ELISA, flow cytometry, chromatin immunoprecipitation, and luciferase reporter assays, we demonstrate that TIPE2 deficiency significantly reduces LRRC33 expression and surface TGF-β1 localization, thereby suppressing tumor growth. We further show that STAT3 transcriptionally upregulates TIPE2 in MDSCs, and its pharmacological inhibition phenocopies TIPE2 loss, reducing TGF-β1 bioavailability and synergizing with anti-PD-1 therapy to enhance antitumor immunity and reshape the TME. These findings identify the STAT3-TIPE2-LRRC33 axis as a novel intracellular checkpoint governing localized TGF-β1 activation and provide a compelling rationale for targeting this pathway to improve response to PD-1 blockade in lung cancer.