This article systematically reviews the mechanisms by which solid compressive stress arises in solid tumors, its biological effects, and its impact on tumor progression and therapy resistance, proposing combination therapeutic strategies targeting the mechanical tumor microenvironment.
Literature Overview
This article, 'Compressive stresses in cancer: characterization and implications for tumour progression and treatment,' published in Nature Reviews Cancer, reviews and summarizes the sources of solid compressive stress within the tumor microenvironment, cellular mechanosensing mechanisms, its regulatory role in cancer cell fate, and its critical involvement in treatment resistance. The article systematically explains how mechanical forces promote tumor progression by influencing cell cycle, epigenetics, metabolism, and stemness, and explores the therapeutic potential of targeting the mechanical microenvironment. The entire section is coherent and logically structured, ending with a Chinese period.Background Knowledge
Abnormal physical features of the tumor microenvironment are key drivers of cancer progression and therapy resistance. Among these, solid compressive stress—caused by tumor cell proliferation, extracellular matrix deposition, and confinement from surrounding tissues—can reach several kilopascals, significantly higher than in normal tissues. This mechanical force not only alters cell morphology and structure but also triggers signaling pathways via mechanosensitive channels (e.g., YAP, PIEZO1, TRPV4), thereby regulating gene expression, inducing cell cycle arrest, reprogramming metabolism, and promoting stemness. Previous studies have shown that compressive stress can induce cellular quiescence, enhance resistance to chemotherapy and radiotherapy, and promote immune evasion and vascular dysfunction. However, due to technical limitations, precise in vivo measurement and modulation of compressive stress remain challenging. Current research largely relies on in vitro models (e.g., colloidal confinement, osmotic compression) or computational simulations, lacking direct correlation analyses between stress distribution and pathological phenotypes in clinical samples. Furthermore, how to effectively alleviate intratumoral solid stress and synergistically enhance the efficacy of existing therapies remains an urgent challenge. This review integrates recent advances in the field of tumor mechanobiology, providing a theoretical framework and potential targets for developing novel 'mechano-therapeutic' strategies.
Research Methods and Experiments
The authors comprehensively analyzed recent studies on the mechanical tumor microenvironment, including in vitro compression models (e.g., weight-mediated compression, osmotic pressure application, cell confinement within matrices), in vivo models (e.g., magnetic bead manipulation, surgical implantation, screw devices), and computational modeling approaches (based on tissue deformation, fluorescent microbead displacement, or incision-relaxation for stress calculation). By integrating multiple technical approaches, the biological impacts of compressive stress on both cancer and stromal cells were systematically evaluated.Key Conclusions and Perspectives
Research Significance and Prospects
This study emphasizes solid compressive stress as a key driver of tumor progression, revealing its multifaceted roles in regulating cell fate, promoting heterogeneity, and mediating therapy resistance. By systematically outlining the mechanisms of mechanical signal sensing and transduction, it provides a theoretical foundation for developing novel therapeutic strategies targeting the physical tumor microenvironment.
Future research should focus on developing non-invasive technologies for real-time monitoring of intratumoral stress distribution and exploring more precise mechanical interventions. Combining mechano-modulatory agents with conventional therapies (e.g., chemotherapy, radiotherapy, immune checkpoint inhibitors) holds promise for overcoming microenvironment-mediated resistance and improving treatment outcomes. Additionally, individualized assessment of tumor mechanical properties may emerge as a novel biomarker for predicting therapeutic response.
Conclusion
This article comprehensively summarizes the sources and biological effects of solid compressive stress in solid tumors, and its profound impact on cancer progression and treatment response. Compressive stress not only directly suppresses cancer cell proliferation, induces quiescence and stemness, and enhances therapy resistance, but also promotes tumor heterogeneity and invasiveness by altering nuclear structure, chromatin states, and metabolic reprogramming. Simultaneously, it disrupts vascular function, limits drug delivery, and fosters an immunosuppressive microenvironment. These findings underscore the mechanical microenvironment as a crucial therapeutic target. Targeting mechanosensory pathways (e.g., YAP, PIEZO1) or alleviating stromal contraction (e.g., with ATRA) may reverse compression-induced drug-resistant phenotypes and enhance the efficacy of existing therapies. Future efforts should focus on developing advanced technologies to quantify mechanical stress in clinical samples and advance the translational application of 'mechano-therapeutic' strategies, offering new combination treatment options for cancer patients. This study provides a systematic framework for understanding the network of mechanical regulation in tumors, with significant theoretical and clinical implications.
