RHEB-CSF1R signaling, autophagy, and metastatic plasticity in pancreatic cancer: Current advances, controversies, and translational opportunities

Table 1 Representative studies supporting the ras homolog enriched in brain-colony stimulating factor 1 receptor-phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin-autophagy framework in pancreatic ductal adenocarcinoma

Ref.	Study type	Molecule/pathway	Principal finding	Relevance to PDAC progression/metastasis	Translational implication
Tan et al[12], 2021	Bioinformatics + cell assays	RHEB	RHEB is overexpressed in PDAC and promotes proliferation, migration, and invasion, with additional links to cell-cycle regulation and Wnt signaling	Supports RHEB as a pro-aggressive signaling node in PDAC	Potential prognostic biomarker and pathway target
Deng et al[23], 2026	Tissue, cell, and in vivo study	RHEB-CSF1R/PI3K/AKT/mTOR	Proposed a tumor-cell RHEB-CSF1R complex that enhances PI3K/AKT/mTOR phosphorylation, suppresses autophagy-associated programs, and promotes EMT and metastasis	Directly links RHEB-centered signaling to metastatic behavior	Provides a biomarker-driven and combination-targeting hypothesis
Zhu et al[25], 2014	Preclinical PDAC model	CSF1/CSF1R-TAM axis	CSF1R blockade reprograms TAMs and improves the response to T-cell checkpoint immunotherapy	Demonstrates macrophage-driven support of progression and immune escape	Supports CSF1R-directed microenvironmental therapy
Mitchem et al[26], 2013	Preclinical PDAC model	CSF1R-TAM axis	Targeting TAMs reduces tumor-initiating cells, relieves immunosuppression, and enhances response to chemotherapy	Supports a metastasis-promoting role of macrophage-rich microenvironments	Supports combining CSF1R/TAM-directed therapy with cytotoxic treatment
Chen et al[10], 2023	Multi-omics analysis	Autophagy-related genes, including RHEB	Constructed an autophagy-related mRNA/miRNA/transcription factor/immune-cell network and identified RHEB among key autophagy-related hub genes	Supports the prognostic and regulatory relevance of autophagy-associated signaling in PDAC	Suggests candidate autophagy-modulator targets
Deng et al[13], 2025	Bioinformatics	Five autophagy-related genes, including RHEB	Developed a five-gene autophagy-related prognostic model with potential relevance to immune targeting	Supports the association between RHEB-centered signatures and immune infiltration	Suggests potential immunotherapy-oriented biomarker development

RHEB: Ras homolog enriched in brain; CSF1R: Colony stimulating factor 1 receptor; PDAC: Pancreatic ductal adenocarcinoma; AKT: Protein kinase B; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mammalian target of rapamycin; TAM: Tumor-associated macrophage; EMT: Epithelial-mesenchymal transition.