Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy

• Published in: Advanced drug delivery reviews Vol. 186; p. 114319
• Main Authors: Zhang, Tian, Jia, Yuanbo, Yu, Yang, Zhang, Baojun, Xu, Feng, Guo, Hui
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.07.2022
• Subjects: Biophysical cues; Mechano-nanomedicine; Targeting strategies; Therapeutic resistance; Tumor microenvironment; Targeting strategies; Tumor microenvironment; Therapeutic resistance; Biophysical cues; Mechano-nanomedicine
• ISSN: 0169-409X; 1872-8294
• DOI: 10.1016/j.addr.2022.114319

Biophysical cues in tumor microenvironment involved in the cascade of anti-tumor immunity and immunotherapy. a. The basis of tumor immunotherapy is a complete, self-propagating cyclical process known as anti-tumor immunity, the core function of which is to kill cancer cells through the anti-cancer immune response. Biophysical cues induce immunotherapy resistance by interfering with the complete progress of the anti-tumor immunity cascade. The upper box represents the specific steps of the anti-tumor immunity response, and the colored blocks in the lower box represent the biophysical cues that mainly affect this step and its consequences. b. The goal of cancer immunotherapy is to initiate and amplify a self-sustaining anti-tumor immunity cycle. ICBs-based immunotherapy plays such a role by blocking checkpoints and restoring T cell function. It is crucial for therapeutic antibodies to successfully enter the tumor and be maintained in an effective concentration. The IFP in the TME is high in the center and low at the edges. The blue gradient background represents the change in IFP. The steep IFP gradient drives the tumor interstitial fluid toward the periphery. Outward fluid flow will remove tumor therapeutic antibodies and reduce the length of time antibodies are retained. The dense ECM is a physical barrier to the diffusion of therapeutic antibodies as well. [Display omitted] 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.