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.