Table 2.

Summarizing the PDAC Features Effecting Tumor Perfusion and Penetration and Potential Solutions

Key Features of PDAC	Mechanisms	Impact on Different Therapeutics	Potential Strategies to Enhance Penetration
Highly dense stroma (Increased stiffness and solid stress)	- Excessive ECM production by CAFs - Reduced ECM degradation - Crosslinked matrix - Contractile CAFs	Poor diffusion and penetration of - Macromolecules, eg, monoclonal antibodies - Nanomedicine	- Inducing ECM degradation - Targeting CAFs (inhibit CAF-induced matrix production and CAF contraction)
Compressed and collapsed vasculature	- Infantile vasculature - High interstitial fluid pressure - Non-functional lymphatics	Poor perfusion of - Small drug molecules, eg, chemotherapeutics - Nanomedicine	- Reduce IFP using hypotensive agents - vasculature normalization
Poor EPR* effect	- Compressed and collapsed blood vessels - Excessive matrix deposition	Reduced extravasation - Macromolecules, eg, monoclonal antibodies - Nanomedicine	- Improve blood perfusion, eg, normalization of vasculature - Enhance ECM degradation and inhibit ECM deposition
Immuno-suppressive environment	- Interaction between TAMs and cancer cells - Dense stroma	- Poor immuno-surveillance and efficacy of immunotherapy, eg, cell-based therapies and checkpoint inhibitors	- Targeting immune cells, eg, reprogram TAMs into anti-tumoral type - Anti-stromal agents to enhance penetration

Abbreviation: *EPR, Enhanced Permeability and Retention effect.