Intratumoral viable biological agent as a Multi-Mechanism Therapeutic Strategy for Pancreatic Adenocarcinoma

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits five-year survival rates below 10% with profound therapeutic resistance mediated by stromal barriers and immunosuppression [1,2]. Recent evidence suggests intratumoral mycobiome alterations may influence disease progression [17,18]. Methods: We performed comprehensive network pharmacology analysis to elucidate potential therapeutic mechanisms of Saccharomyces boulardii (SB) and Clostridium histolyticum collagenase (CHC) in PDAC. Gene sets representing immune activation, metabolic competition, and stromal remodeling were analyzed using protein-protein interaction networks (STRING v11.5), functional enrichment (DAVID v2021), and pathway databases (KEGG, Reactome, WikiPathways, DisGeNET). Results: Network analysis identified dense interconnectivity among 20 core immune-metabolic genes with hub proteins TNF, IL6, IFNG, and TLR4 (degree >15). Key intersecting genes between SB and CHC mechanisms included IL6, TLR2, MMP9, and IL1B. Pathway enrichment revealed significant involvement in IL-17 signaling pathway (hsa04657), Toll-like receptor signaling (hsa04620), viral protein interaction with cytokines (hsa04061), interleukin-10 signaling (fold enrichment = 184.61, p=4.47×10−31 p =4.47×10−31), and immune infiltration in pancreatic cancer (WP5285). Co-occurrence analysis across 10,897 tumors revealed coordinated expression of IFNG-TLR4 and IFNG-CD86 gene pairs. Conclusions: Network analysis supports biological plausibility of multi-mechanism SB anti-tumor activity through convergent immune activation, metabolic competition, and stromal remodeling pathways complemented by CHC-mediated extracellular matrix disruption. This systems-level framework provides mechanistic rationale for empirical investigation.