Suppression of tumor growth by GMI, an edible fungal immunomodulatory protein, is associated with targeting GSK3β‑mediated proteasomal degradation of PD‑L1.

Cancer cells evade T cell responses by exploiting programmed death‑ligand 1 (PD‑L1) in the tumor microenvironment, and oncogenic epidermal growth factor receptor (EGFR) signaling stabilizes PD‑L1 expression. immunomodulatory protein (GMI), a consumable mushroom‑derived dietary supplement, functions as an EGFR degrader targeting EGFR‑positive cancer cells. However, the role of GMI in regulating PD‑L1 and modulating antitumor immunity has not been fully elucidated. In the present study, functional enrichment analysis was first employed to investigate GMI‑regulated differentially expressed proteins. The findings indicated that GMI may modulate the PD‑L1 signaling pathway. GMI downregulated PD‑L1 expression by regulating both mRNA and protein stability, thereby suppressing PD‑L1‑positive lung cancer cells and . Functional studies further demonstrated that GMI promotes glycogen synthase kinase 3 beta (GSK3β)‑mediated proteasomal degradation of PD‑L1. Knockdown of GSK3β in lung cancer cells abolished the GMI‑induced reduction in PD‑L1 expression. Additionally, GMI inhibited tumor growth and reduced PD‑L1 levels in allograft mouse models. Importantly, GMI‑mediated PD‑L1 downregulation correlated with enhanced T cell‑mediated inhibition of lung cancer cells. These findings shed light on the potential of edible GMI to boost antitumor immunity.