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

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.