Review Highlights Tumor Microenvironment Features Contributing to Immunotherapy Resistance

Treatment resistance is a significant challenge in immunotherapy, but it is not fully understood. A recent review summarized 5 tumor microenvironment traits that may inhibit therapy effectiveness and potential strategies to improve therapy responses.

Immunotherapy has significantly advanced the treatment landscape for certain cancer types, but treatment resistance is a challenging barrier that is not yet fully understood. A recent review delved into the biophysical cues that precede immunotherapy resistance in cancer cells and the ways in which they affect therapy efficacy.

Immunotherapy resistance, whether primary or acquired, can be difficult to manage, but there are known and suspected tumor microenvironment (TME) characteristics that can come into play for both resistance and response to treatment. The review, published in Advanced Drug Delivery Reviews, discusses abnormalities in the TME that may affect a patient’s response to immunotherapy. These include the structure of the extracellular matrix (ECM), ECM stiffness, tumor interstitial fluid pressure (IFP), solid stress, and variable vascular shear stress.

Each of these biophysical cues has potential to disrupt immunotherapy efficacy by interrupting the process of anti-tumor immunity, which would otherwise be a self-propagating cyclical process that kills cancer cells when a patient’s disease is not resistant to therapy.

Physical Microstructure of the ECM and ECM Stiffness

The structure of the ECM, which serves as a physical barrier as cells attempt to enter a tumor, can obstruct active and proliferating T cells from penetrating tumor cells. One of the mechanisms of this type of resistance is densely crosslinked collagen fibers in the ECM, and this type of resistance is prominent in tumors such as pancreatic, breast, and prostate cancers. With PD-L1 or PD-1 inhibition, for example, the size and shape of the drug can prevent it from entering through dense ECM structures.

Many solid tumors are also characterized by ECM stiffness, with tissue 5- to 10-times stiffer than normal tissue. In tumor cells, increased stiffness has been shown to upregulate PD-L1 expression due to F-actin polymerizing, but how and why the F-actin pathway affects PD-L1 expression is not clear. ECM stiffness in the TME also affects the role of immune cells, including natural killer cells, in the anti-tumor immunity process and can contribute to treatment resistance.

Treatments to reduce the amount of collagen in the TME, such as lysyl oxidases inhibitors or agents to target cancer-associated fibroblasts (CAFs), could potentially improve immunotherapy in cases of dense ECM structures. Nanomaterials to degrade ECM directly could also hold promise. For ECM stiffness, study authors highlight the potential of TGF-β blockade, as TGF-β plays a part in converting fibroblasts into CAFs. Other proteins affecting CAFs may also serve as targets.

Tumor IFP

The interstitial fluid osmotic pressure and hydrostatic pressure have a significant role in determining the homeostasis of IFP, and most normal tissues have close to 0 IFP. Malformed tumor blood vessels and lymphatic vessels, abnormal ECM, and various cytokines contribute to an increase in IFP. When IFP is high in tumor islands and low in peripheral tumor cells, abnormal interstitial fluid flow can prevent therapeutic antibodies from reaching their targets efficiently and reduce the effects of immunotherapy.

To target IFP, the authors highlight vascular endothelial growth factor (VEGF) inhibition and platelet-derived growth factor (PDGF) inhibition. Both VEGF and PDGF can increase IFP through different mechanisms, and both have potential as targets to improve immunotherapy response. Research has shown that targeting both simultaneously had an even more significant effect on IFP but did not further improve response to chemotherapy in mouse studies. Hyaluronidase is another agent that can degrade the ECM and reduce IFP pressure, potentially increasing drug absorption.

Solid Stress

Solid stress occurs when cell proliferation, matrix deposition, swelling, and increased tumor tissue volume in a limited environment force interaction between surrounding normal tissue and tumor tissue. This can activate the PI3K/Akt pathway in tumor cells, which can upregulate anti-apoptotic molecules and prevent tumor cell death.

Considering the overall effect of solid stress on the TME, one potential treatment strategy could be immune checkpoint blockades plus PI3K-Akt-mTOR inhibition, although study authors note that the risk of serious immune-related adverse events may increase with this type of treatment.

FAK inhibitors have been tested in mice and can reduce solid stress, potentially leading to better immunotherapy response. TGF-β blockade is another possible strategy, especially given its potential as a multi-functional tool that also affects the ECM.

Variable Vascular Shear Stress

Shear stress affecting cells in fluid as well as vascular endothelial cells can occur in tumors with blood vessels that were formed quickly and are immature. Circulating tumor cells can form clusters under shear stress that protect them from damage by the stress, but these clusters can also help them avoid immune surveillance. While there is no targeted treatment for vascular shear stress, the treatments for solid stress reduction and blood vessel normalization could help improve the vascular shear stress in the TME. Drugs to promote vasodilation may also help lower vascular shear stress but have not been used specifically in cancer treatment yet, the authors noted.

Finally, the authors highlight a need for better tools to explore the mechanisms of immunotherapy resistance due to the biophysical cues contributing to it. Their hope is that the review will draw attention to the need for new in vivo and in vitro model systems to research the effects of these biophysical cues.

“Increasing awareness of the significance of TME in cancer progression would help researchers find new targets and treatment strategies with which to improve treatment efficacy,” the authors wrote. “Importantly, this requires not just a thorough grasp of cancer’s physical and biochemical features, but also close cooperation among oncologists, clinicians, physical scientists and data scientists in the field of engineering.”


Zhang T, Jia Y, Yu Y, Zhang B, Xu F, Guo H. Targeting the tumor biophysical microenvironment to reduce resistance to immunotherapy. Adv Drug Deliv Rev. Published online May 8, 2022. doi:10.1016/j.addr.2022.114319