Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy

Abstract

The interplay between extracellular matrix (ECM) stiffness and the tumor microenvironment is increasingly recognized as a critical factor in cancer progression and the efficacy of immunotherapy. This review comprehensively discusses the key factors regulating ECM remodeling, including the activation of cancer-associated fibroblasts and the accumulation and crosslinking of ECM proteins. Furthermore, it provides a detailed exploration of how ECM stiffness influences the behaviors of both tumor and immune cells. Significantly, the impact of ECM stiffness on the response to various immunotherapy strategies, such as immune checkpoint blockade, adoptive cell therapy, oncolytic virus therapy, and therapeutic cancer vaccines, is thoroughly examined. The review also addresses the challenges in translating research findings into clinical practice, highlighting the need for more precise biomaterials that accurately mimic the ECM and the development of novel therapeutic strategies. The insights offered aim to guide future research, with the potential to enhance the effectiveness of cancer immunotherapy modalities.

Fig. 1. Key factors driving ECM stiffness.

The primary contributors to ECM stiffness include the activation of CAFs, excessive deposition of ECM components, and enhanced collagen crosslinking.

Fig. 2. Increased ECM stiffness mediates the aggressive phenotype of cancer cells.

Elevated ECM stiffness induces morphological changes in tumor cells, primarily in the form of pseudopodia formation, expanded spreading areas, and enhanced cell adhesion. These changes promote cancer cell proliferation. Additionally, an increase in ECM stiffness drives metabolic reprogramming in cancer cells. Furthermore, EMT facilitated by ECM stiffness contributes to distant metastasis through a sequence of stages. Notably, increased ECM stiffness creates a physical barrier in the TME, which enhances drug efflux, reduces immune cell cytotoxicity, and impedes the infiltration of oxygen, drugs, and immune cells.

Fig. 3. Mechanical forces influence immune cell movement and functionality.

A Force changes detected by immune cell integrins drive movement through retrograde F-actin flow, connected by myosin II. B Membrane tension opens ion channels on immune cells, converting extracellular mechanical cues into intracellular biochemical signals via ion influx. C Under force, immune cells connect to epithelial cells via selectins and roll on their surfaces. At specific sites, immune cell integrins bind to receptors on epithelial cells. Post-adhesion, immune cells develop invadopodia-like protrusions (ILPs), aiding in transmigration. D Antigen recognition necessitates direct contact between T cells and APCs. Mechanical forces influencing receptor-ligand bond formation affect the formation of the immunological synapse. LFA1, the primary integrin on T and B cells, binds tightly to adhesion molecules ICAM1 and ICAM2 on APCs, governing mechanosensitive antigen recognition. E B cells selectively internalize high-affinity antigens via myosin IIa-driven contraction, pulling and invaginating the presenting membranes. F CTLs tighten synapses on target cell membranes by applying force, promoting perforin’s pore-forming activity, and enhancing cytotoxicity.

Fig. 4. Overview of cellular mechanisms in immune cells influenced by varying ECM stiffness.

In soft ECM environments, there is enhanced T cell proliferation and guidance of CD8⁺ T cell activation, migration, and infiltration. Conversely, a stiff ECM hinders T cell proliferation and reduces CD8⁺ T cell mobility and cytotoxicity. Low ECM stiffness steers naive CD4⁺ T cells toward Th1 polarization and promotes M1 macrophage polarization from M0, aiding in anticancer immune effects. High ECM stiffness directs immature CD4⁺ T cells to Th2 polarization and M2 macrophage polarization from M0, fostering pro-cancer TME effects.

Fig. 5. Targeting ECM stiffness for improving the efficacy of immunotherapy.

A Mechanisms and strategies to counter high ECM stiffness in ICB. Elevated ECM stiffness modulates the expression of ICs through mechanotransduction signaling pathways. ICIs delivery is enhanced when combined with ECM remodeling agents like MMP and LOX inhibitors, enhancing ICB therapeutic efficacy. B Physical factors impeding CAR-T cell delivery and corresponding strategies. In tumors with high ECM stiffness, CAF encapsulation and abnormal vasculature obstruct CAR-T cell infiltration and lead to T-cell exhaustion. Targeting specific proteins, such as EDA, EDB, or CAF marker FAP, facilitates CAR-T cell penetration, effectively curtailing tumor growth. C Physical barriers to OV delivery and strategies to overcome them. The stiff ECM barrier hinders OVs from reaching tumor cells. Pairing OVs with ECM-degrading proteins, such as MMPs, hyaluronidase, or relaxin, breaks down this barrier, amplifying the OV’s cytotoxic effects by T-cell activation and self-replicating. D Therapeutic strategies for overcoming high ECM stiffness impeding TCV delivery. The stiff ECM barrier hampers TCV effects. TCVs combined with ECM-degrading agents promote antigen presentation of DCs and stimulates the activation of CD8⁺ T cell, thereby intensifying their cytotoxicity against cancer cells.