Background/Objectives: Mesenchymal stem cells (MSCs) possess immunomodulatory properties, tumor-homing, and low immunogenicity, making them attractive for cell-based cancer therapies, but their role in colorectal cancer (CRC) remains controversial. The MSC1 phenotype, a pro-inflammatory, tumor-suppressive state induced by short-term, low-dose LPS activation via TLR4, has shown therapeutic promise but remains poorly characterized in CRC. We aimed to elucidate MSC1’s tumor-suppressive mechanisms and validate its activity against CRC cells using an integrated bioinformatics and in vitro approach. Methods: We constructed a high-confidence protein-protein interaction (PPI) network in Wharton’s jelly-derived MSCs (WJ-MSCs) following TLR4 activation to uncover enriched signaling pathways, transcriptional regulators, and secreted factors. Functional and transcriptional enrichment analyses pinpointed key mechanisms. We then co-cultured MSC1 cells with CRC cells to assess effects on proliferation and metabolism. Results: Network analysis revealed six tumor-suppressive mechanisms of MSC1 cells: (i) Metabolic reprogramming via enhanced glucose and lipid uptake, phosphoinositide signaling, and membrane/protein recycling, (ii) Robust antioxidant defenses, including SOS signaling and system xc⁻, (iii) Extracellular matrix stabilization and laminin-111–integrin-mediated adhesion, (iv) Secretome with direct anti-cancer effects, (v) Regulation of survival and cancer-associated fibroblasts (CAFs) formation inhibition through balanced proliferation, apoptosis, and epigenetic signals, (vi) Controlled pro-inflammatory signaling with anti-inflammatory feedback. In vitro, MSC1 cells significantly suppressed CRC cell proliferation and metabolic activity versus controls. Conclusions: This study provides the first mechanistic map of MSC1’s tumor-suppressive functions in CRC, extending beyond immunomodulation to include metabolic competition, ECM stabilization, and anti-cancer secretome activity. These findings establish MSC1 cells as a novel therapeutic strategy for CRC in cell-based cancer therapies.

Acquired resistance to EGFR tyrosine kinase inhibitors remains a principal barrier to durable remission in non-small cell lung cancer (NSCLC). Using a time-resolved protein interaction network analysis of isogenic Gefitinib-sensitive and resistant NSCLC cells, we show that network entropy increases progressively under drug treatment in both phenotypes, while small-world topology is lost, consistent with Gefitinib's dismantling of EGFR-centered signaling hubs. Eigenvector entropy alone distinguished the resistant phenotype at baseline, reflecting a pre-established, robustly buffered network state. Co-expression network analysis revealed a resistance-specific subnetwork in which delta-catenin (CTNND1) serves as the dominant topological bridge between EGFR, VAV3, HIF3A, and NOTCH2, four nodes independently linked to chemoresistance but not previously connected within a single regulatory network. We propose that HIF1α-driven induction of CTNND1, EGFR-mediated positive feedback, and VAV3-dependent Rho-GTPase activation cooperate to drive actin cytoskeletal remodeling and phenotypic switching. BIRC3 emerged as an independent late-stage apoptotic block exclusive to resistant cells. These findings nominate CTNND1 and VAV3 as candidate co-targets and eigenvector entropy as a systems-level biomarker of Gefitinib resistance.