Stroma-nerve axis in pancreatic ductal adenocarcinoma: Bidirectional regulatory mechanisms and clinical translation hypothesis

Table 1 Key controversies, conflicting evidence, and stroma-nerve axis framework explanatory hypotheses

Controversial point	Supporting evidence (A)	Conflicting evidence (B)	SNA framework explanatory hypothesis (mechanistic detail)
Stromal depletion	FAP+ cell depletion or enzymatic degradation (e.g., PEGPH20) enhances drug delivery in select murine models[38]	Phase III HALO-301 trial failed to show survival benefit and paradoxically increased adverse events[9]	Disruption of mechanical restraint: Aggressive depletion in SNA-II (stroma-dominant) tumors may compromise the physical “capsule” that restrains tumor spread, as seen in α-SNA depletion models[91,92]. SNA theory favors “stromal normalization” over ablation to improve perfusion without breaching the barrier
Parasympathetic role	Activation of muscarinic receptors (e.g., M3R) promotes tumor cell proliferation and invasion in vitro[37]	Vagotomy (parasympathetic denervation) accelerates pancreatic cancer progression and metastasis in animal models[22]	Pathway context-dependency: The cholinergic anti-inflammatory pathway likely inhibits SNA-II associated inflammation. Thus, systemic vagotomy removes this “brake”, worsening the microenvironment. SNA theory posits that parasympathetic effects depend on the balance between direct tumor stimulation and indirect immune modulation
Neural blockade efficacy	Surgical or chemical denervation significantly slows tumor initiation and progression in genetically engineered mouse models[24]	Clinical trials targeting nerve signaling (e.g., neurolytic celiac plexus block) have largely failed to extend survival in unselected patients[95]	Dilution effect in unselected cohorts: Current trials treat PDAC as a uniform entity. We hypothesize that only SNA-I (nerve-dominant) tumors possess the high neurotrophic dependency required for response. In contrast, SNA-II tumors are driven by stromal signaling, rendering them refractory to neural blockade alone

This table synthesizes conflicting evidence to demonstrate how the stroma-nerve axis framework resolves paradoxes through subtype-specific mechanisms, such as distinguishing mechanical restraint in stroma-dominant tumors from neurotrophic dependency in nerve-dominant ones. FAP: Fibroblast activation protein; PEGPH20: Pegylated recombinant human hyaluronidase; M3R: Muscarinic acetylcholine receptor 3; SNA: Stroma-nerve axis; SMA: Smooth muscle actin; PDAC: Pancreatic ductal adenocarcinoma.