Biomechanics in the tumor microenvironment: from biological functions to potential clinical applications

Abstract

Immune checkpoint therapies have spearheaded drug innovation over the last decade, propelling cancer treatments toward a new era of precision therapies. Nonetheless, the challenges of low response rates and prevalent drug resistance underscore the imperative for a deeper understanding of the tumor microenvironment (TME) and the pursuit of novel targets. Recent findings have revealed the profound impacts of biomechanical forces within the tumor microenvironment on immune surveillance and tumor progression in both murine models and clinical settings. Furthermore, the pharmacological or genetic manipulation of mechanical checkpoints, such as PIEZO1, DDR1, YAP/TAZ, and TRPV4, has shown remarkable potential in immune activation and eradication of tumors. In this review, we delved into the underlying biomechanical mechanisms and the resulting intricate biological meaning in the TME, focusing mainly on the extracellular matrix, the stiffness of cancer cells, and immune synapses. We also summarized the methodologies employed for biomechanical research and the potential clinical translation derived from current evidence. This comprehensive review of biomechanics will enhance the understanding of the functional role of biomechanical forces and provide basic knowledge for the discovery of novel therapeutic targets.

Keywords: Biomechanical target; Biomechanics; Extracellular matrix; Stiffness; Tumor microenvironment.

Fig. 1

The complex mechanical perturbations within the tumor microenvironment. The TME is an intricate ecosystem comprising tumor cells, endothelial cells, stromal cells, diverse immune cells, and the extracellular matrix. In this context, the stiffness of cancer cells decreases, while the stiffness of the ECM increases, leading to an elevation in IFP. This, in turn, impedes the delivery of nutrients and oxygen, and promotes the accumulation of metabolic waste, ultimately obstructing the delivery of anti-cancer drugs to the tumor region. The cancer cells of the primary tumor site invade and enter the circulatory system to form CTCs. On the one hand, other cells in the bloodstream protect CTCs from FSS by encapsulating them; on the other hand, tumor cells also adjust their own stiffness to adapt to FSS. In addition, FSS also regulates the cell cycle of CTCs. Furthermore, the mechanical disturbances within the TME also compromise the infiltration of immune cells and their cytotoxic capabilities through inducing immune cell exhausted and unstable immune synapses. TME tumor microenvironment, ECM extracellular matrix, IFP interstitial fluid pressure, CTCs circulating cancer cells, FSS fluid shear forces

Fig. 2

Schematic diagram of the immune synapses. The immune synapse is the structural basis for lymphocytes to receive antigen presentation and effector functions by secreting lytic granules. The arrow on the right panel indicates the direction of retrograde F-actin flow. dSMAC distal supramolecular activation cluster, cSMAC central supramolecular activation cluster, pSMAC peripheral supramolecular activation cluster

Fig. 3

Overview of cellular mechanotransduction pathways. Mechanical force or a stiff ECM stimulates membrane mechanoreceptors, triggering a cascade of downstream reactions: (i) Activated integrins anchor to the ECM, forming focal adhesions and recruiting FAK and SRC to form a complex that activates the Rho protein family, thereby altering the disassembly and assembly of actin filaments. The polymerization of F-actin reduces the availability of G-actin, decreasing its binding to MRTFA. MRTFA then translocates to the nucleus and co-participates with SRF in gene transcription; (ii) Phosphorylated and activated DDR interacts with MLCK, thereby activating myosin; (iii) The cation channels TRPV4 and Piezo1 are activated by mechanical stimuli, promoting Ca2⁺ influx; (iv) The unphosphorylated YAP/TAZ translocates to the nucleus, where it binds to the TEAD family members to form a functional transcriptional complex, promoting the expression of downstream genes; (v) The cytoskeleton can transmit extracellular physical stimuli directly to the nucleus by connecting one end to adhesion structures on the cell membrane and the other end to the nuclear lamin proteins A/C through the LINC complex. ECM extracellular matrix, LINC the linker of nucleoskeleton and cytoskeleton complex

Fig. 4

The timeline of important techniques in biomechanical research

Fig. 5

Diagnosis and treatment based on the mechanical characteristics of tumor and immune cells. Magnetic resonance and ultrasound elastography can help detect changes in tumor stiffness. Enhancing the stability of the immune synapse and tumor cell stiffening can improve the efficacy of tumor immunotherapy. Remodeling the ECM and the use of novel matrix materials can facilitate immune cell infiltration and drug release. Combination therapy targeting mechanosensors can improve tumor prognosis. ECM extracellular matrix