fig3
Figure 3. Therapeutic strategies targeting the PDAC resistance ecosystem. Therapeutic approaches directed at the PDAC resistance ecosystem aim to reprogram, rather than indiscriminately eliminate, tumor microenvironmental components and resistance-supporting processes. Stromal and ECM modulation seeks to reprogram CAF/PSC activity, remodel the ECM, and improve vascular function through pathways including TGF-β, FAK, and VDR; importantly, PEGPH20-mediated hyaluronan depletion failed to improve survival in a phase III PDAC trial, highlighting the limitations of indiscriminate stromal depletion. Additional investigational strategies include targeting hypoxia and acidosis, reprogramming immunosuppressive myeloid populations and enhancing T-cell function, disrupting metabolic dependencies and metabolic–immune crosstalk, inhibiting cytoprotective autophagy and exploiting ferroptotic vulnerability, and modulating the microbiome. These approaches may help control tumor growth, improve drug delivery, enhance antitumor immunity, reduce resistance phenotypes, and increase therapeutic sensitivity. Overall, mechanism-guided and biomarker-informed combination strategies may enable more effective targeting of the interconnected PDAC resistance ecosystem; however, many of these approaches remain investigational and should not be interpreted as having established clinical efficacy. PDAC: Pancreatic ductal adenocarcinoma; ECM: extracellular matrix; CAF: cancer-associated fibroblast; PSC: pancreatic stellate cell; TGF-β: transforming growth factor-β; FAK: focal adhesion kinase; VDR: vitamin D receptor; PEGPH20: pegylated recombinant human hyaluronidase; TME: tumor microenvironment; HA: hyaluronan; HIF: hypoxia-inducible factor; CAIX: carbonic anhydrase IX; CCR2: C-C motif chemokine receptor 2; CXCR4: C-X-C motif chemokine receptor 4; LDHA: lactate dehydrogenase A; CQ: chloroquine; HCQ: hydroxychloroquine; system Xc-: cystine/glutamate antiporter; SLC7A11: solute carrier family 7 member 11; GPX4: glutathione peroxidase 4.
