Identification of autophagy-related immune targets for enhancing immunotherapy in pancreatic cancer aggressiveness.

BACKGROUND: Pancreatic cancer (PC) presents significant challenges in oncology, with metastasis critically affecting patient outcomes. Autophagy-related genes (ARGs)'s involvement in influencing immune activity and metastasis in PC remains inadequately understood. AIM: This study seeks to identify and validate five ARGs that could serve as immune targets, enhancing enhancing Pancreatic cancer metastasis (PCM)'s prognostic models and informing immunotherapy strategies. METHODS: ARGs that were diffentially expressed were screened, followed by Cox regression and LASSO analyses to pinpoint five genes linked to overall survival (OS). A prognostic model was developed and validated using ROC curves. Functional analyses, including GO and KEGG, were performed to elucidate ARG mechanisms. Immune infiltration and TFs/microRNA/mRNA networks were assessed to understand ARG-immune cell interactions. Experimental validation employed real-time PCR, IHC, and Western blotting, supported by TCGA data. Functional assays explored RHEB's role in PC, particularly its interaction with LC3. RESULTS: Five ARGs (CASP1, RHEB, CHMP2B, MYC, and HDAC6) were identified, contributing to a robust prognostic model where low-risk individuals showed significantly longer OS. The model demonstrated high AUC scores, indicating strong prognostic capability. CD8 T cells and Treg cells' elevated levels were observed in metastatic subjects. RHEB knockdown suppressed cancer cell proliferation and invasion, with a negative correlation between RHEB and LC3, suggesting a role in autophagy-mediated modulation of PC metastasis. CONCLUSION: This study introduces a novel prognostic model incorporating five ARGs, highlighting their potential as immune targets for cancer immunotherapy. The negative correlation between RHEB and LC3 suggests a therapeutic pathway for PCM intervention, laying the groundwork for more effective anti-cancer strategies. These findings advance the identification of novel immune targets and signaling pathways, aligning with precision medicine goals in cancer treatment.