Secretory Lysosome‐Related Gene Signature Defines the Immune Microenvironment and Identifies RGS2 as a Prometastatic Factor in Hepatocellular Carcinoma

Introduction Hepatocellular carcinoma (HCC) is a highly aggressive tumour with significant heterogeneity and a poor response to immunotherapy. Secretory lysosomes (SLs) control immunological responses and cellular homeostasis; however, the significance of secretory lysosome‐related genes (SLRGs) in HCC prognosis and treatment is unclear. This work sought to create a predictive signature based on immune lysosome‐related genes (immLysorgs) and to evaluate RGS2’s functional role in HCC progression. Methods We identified 13 immLysorgs in MSigDB and evaluated genomic and clinical data from the TCGA‐LIHC and GSE76427 cohorts. Molecular subtypes were identified using nonnegative matrix factorization and consensus clustering. A predictive model (immLysoS) was built using LASSO and multivariate Cox regression with four genes: GZMH, KLRB1, RGS2, and SLC6A1. Model performance was validated across multiple cohorts. The involvement of RGS2 in HCC was examined using functional studies such as CCK‐8, colony formation, migration assays, and a xenograft model. Results Two subtypes (C1/C2) and two genotypes (A/B) were found, with the C2 and A groups exhibiting increased survival and immune infiltration. The immLysoS signature efficiently divided patients into risk categories, with low‐risk individuals having much higher overall and progression‐free survival. High immLysoS scores were associated with advanced disease, higher grade, and more TP53 and CTNNB1 mutations. Low‐risk patients responded better to PD‐L1 inhibitors with sorafenib. RGS2 knockdown drastically reduced HCC cell proliferation, migration, and tumor development both in vitro and in vivo. Discussion The immLysoS signature is an effective tool for risk assessment and therapy advice in HCC, as it links SL‐related genes to immunological characteristics and therapeutic response. RGS2 emerges as a possible oncogenic driver and therapeutic target, necessitating additional research into its processes in the HCC microenvironment.