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.

Table 2 Representative small molecules that modulate autophagy-and epithelial-mesenchymal transition-related pathways in pancreatic ductal adenocarcinoma

Agent/target	Signaling pathway	Effect on autophagy	Principal phenotypic effect	Ref.
Umbelliprenin	AKT/mTOR, Notch1	Induces autophagy	Inhibits cancer stemness and induces apoptosis	[42]
Alisertib	PI3K/AKT/mTOR, p38 MAPK, ERK1/2, Sirtuin 1	Induces autophagy	Suppresses EMT and induces cell-cycle arrest	[55]
Qingyihuaji formula	MAPK/ERK, PI3K/AKT/mTOR	Induces autophagy	Induces apoptosis	[44]
Tetrandrine	ROS-related signaling	Inhibits autophagy	Promotes ROS accumulation and enhances therapeutic efficacy	[46]
Rhus coriaria	Not specified	Induces autophagy	Induces apoptosis	[47]
Hernandezine	ROS/AMPK	Induces autophagic cell death	Promotes cancer-cell death	[48]
G6PD	AMPK-mTOR axis	Modulates autophagy	Promotes ferroptosis resistance	[43]
PITPNC1	KRAS-MYC axis	Inhibits autophagy	Links KRAS to MYC and restrains autophagy	[45]

AKT: Protein kinase B; PI3K: Phosphatidylinositol 3-kinase; mTOR: Mammalian target of rapamycin; EMT: Epithelial-mesenchymal transition; MAPK: Mitogen-activated protein kinase; Notch1: Notch homolog 1 (translocation-associated); ERK: Extracellular signal-regulated kinase; ROS: Reactive oxygen species; AMPK: Adenosine monophosphate-activated protein kinase; KRAS: Kirsten rat sarcoma viral oncogene homolog; MYC: Myelocytomatosis viral oncogene homolog.

Table 3 Context-dependent roles of autophagy in pancreatic ductal adenocarcinoma progression

Context	Functional role of autophagy	Mechanistic basis	Biological consequence	Ref.
Basal PDAC state	Tumor-promoting	High basal autophagic activity in PDAC cell lines and patient tissues	Supports tumor growth and metabolic fitness	[38]
Genetic inhibition (ATG7 or HMGB1 knockout)	Functionally tumor-supportive under basal conditions	Autophagy blockade induces ROS accumulation, DNA damage, and metabolic abnormalities	Suppresses PDAC progression	[39]
Pharmacological inhibition (chloroquine)	Functionally tumor-supportive under basal conditions	Pharmacologic blockade disrupts autophagic recycling and promotes oxidative/metabolic stress	Suppresses PDAC progression	[39]
Environmental stress (hypoxia or nutrient deprivation)	Pro-survival	Provides metabolic sub strates and stress adaptation	Supports tumor-cell survival under hostile microenvironmental conditions	[35,72]

PDAC: Pancreatic ductal adenocarcinoma; ROS: Reactive oxygen species.

Table 4 Major controversies and priority future directions in the ras homolog enriched in brain-colony stimulating factor 1 receptor-autophagy field

Key question	Current evidence	Major limitation	Why it matters	Priority next step
Is tumor-cell CSF1R broadly reproducible in PDAC	Recent work suggests that tumor-cell CSF1R may participate in metastatic signaling	CSF1R is classically macrophage-enriched, and tissue-level reproducibility remains uncertain	Determines whether this reflects a tumor-cell mechanism, a microenvironmental signal, or both	Spatially resolved validation using multiplex IF, RNAscope, or scRNA-seq[65]
Is autophagy suppressive or permissive for PDAC metastasis	Available evidence supports a context-dependent dual role of autophagy in PDAC progression[34,35]	Stage, treatment context, and model system can alter interpretation	Directly affects therapeutic strategy	Phenotype-linked, context-aware autophagy studies
Are class I and class III PI3K being conceptually conflated	Class I PI3K–AKT–mTOR signaling is generally linked to autophagy suppression, whereas class III PI3K/VPS34 is required for autophagosome initiation	Many studies refer broadly to PI3K without class-specific clarification	Prevents mechanistic overstatement and improves pathway precision	Class-specific wording and validation
Can RHEB-based signatures improve risk stratification	RHEB is associated with poor prognosis in PDAC datasets and functional models[12]	Existing cohorts remain limited and require independent confirmation	Essential for biomarker development and clinical risk stratification	External validation with C-index, calibration, and time-dependent ROC analysis
What is the most rational translational strategy	CSF1R/TAM, PI3K/mTOR, and autophagy are all targetable in principle	Single-pathway strategies may be insufficient in a highly adaptive tumor	Guides clinical trial design	Evaluate mechanism-driven combinations, including CSF1R-directed therapy with chemotherapy, immunotherapy, or pathway-targeted agents[25,63]

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; IF: Immunofluorescence; VPS34: Vacuolar protein sorting 34; scRNA-seq: Single cell RNA sequencing; ROC: Receiver operating characteristic.