Advances in SEC61G research: from ER translocon subunit to emerging pan-cancer oncogenic roles

SEC61G, the γ subunit of the Sec61 translocon, has long been regarded as a passenger co-amplification target of EGFR on chromosome 7p11.2. Recent studies have revealed its independent oncogenic functions across multiple cancers. This review proposes a mechanism-based classification of SEC61G oncogenic activities: (1) immune checkpoint regulation via canonical translocation; (2) aberrant calcium signaling; and (3) non-canonical mechanisms independent of channel functions. We further delineate the pan-cancer expression and CRISPR-Cas9 dependency landscape, highlighting a dual "high expression, high dependency" profile in cervical squamous cell carcinoma. We distinguish current pore-targeting Sec61 inhibitors from subunit-specific strategies and propose future directions including PROTAC degraders and PPI inhibitors. Our review identifies SEC61G as a pan‑cancer prognostic biomarker and immunotherapy response predictor, with mechanistic evidence supporting its driver roles in glioblastoma, non‑small cell lung cancer, and colorectal cancer, whereas associations in other cancers remain correlative and require further validation.