Figure 2:

Four ways the ECM affects the efficacy of systemic treatment and immunotherapy.

(A) The abundant, rigid, and dense ECM is a diffusion barrier for drug molecules, thus shielding the tumor from the tumor therapy agents and T cells. (B) The ECM also reduces the diffusion of nutrients and oxygen, resulting in a hypoxic and stressful TME. Tumor cells increase the expression of drug efflux pumps, impair apoptosis and senescence, and activate and activate immunosuppressive signaling, rendering drugs that reach the cells less effective. (C) The cell-ECM contact mediated by integrin and FAK signaling inhibits the cytotoxic stress response that avoids cell cycle arrest. (D) Similarly, integrin, FAK, and hyaluronan-induced CD44/HMMR signals can lead to EMT. The mesenchymal state is less proliferative and more chemoresistant. The EMT further increases collagen production and crosslinking (Adapted from Henke et al. [41] with permission).