Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy.

Immunotherapy based on immune checkpoint inhibitors has evolved into a new pillar of cancer treatment in clinics, but dealing with treatment resistance (either primary or acquired) is a major challenge. The tumor microenvironment (TME) has a substantial impact on the pathological behaviors and treatment response of many cancers. The biophysical clues in TME have recently been considered as important characteristics of cancer. Furthermore, there is mounting evidence that biophysical cues in TME play important roles in each step of the cascade of cancer immunotherapy that synergistically contribute to immunotherapy resistance. In this review, we summarize five main biophysical cues in TME that affect resistance to immunotherapy: extracellular matrix (ECM) structure, ECM stiffness, tumor interstitial fluid pressure (IFP), solid stress, and vascular shear stress. First, the biophysical factors involved in anti-tumor immunity and therapeutic antibody delivery processes are reviewed. Then, the causes of these five biophysical cues and how they contribute to immunotherapy resistance are discussed. Finally, the latest treatment strategies that aim to improve immunotherapy efficacy by targeting these biophysical cues are shared. This review highlights the biophysical cues that lead to immunotherapy resistance, also supplements their importance in related technologies for studying TME biophysical cues in vitro and therapeutic strategies targeting biophysical cues to improve the effects of immunotherapy.