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Stress-responsive membrane proteins as execution nodes of tumor cell adaptation to microenvironmental stress

Oncogene (2026)Cite this article

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Abstract

Solid tumors arise within hostile microenvironments shaped by hypoxia, nutrient deprivation, acidosis, mechanical stress, immune pressure, and therapy-induced insults. Beyond malignant cells, stromal and immune components, including cancer-associated fibroblasts, endothelial cells, and infiltrating leukocytes, co-evolve with tumor cells to regulate tumor initiation, progression, and therapeutic response. Rather than passively tolerating stress, tumor cells actively reprogram signaling and transcriptional networks, frequently through the induction of stress-responsive membrane proteins. These proteins are typically low or absent under homeostatic conditions but are upregulated by hypoxic, metabolic, inflammatory, or therapeutic stress. By coordinating nutrient uptake, metabolite exchange, cell-matrix interactions, survival signaling, invasion, and immune evasion, stress-responsive membrane proteins function as critical execution nodes that support tumor stress tolerance and evolutionary fitness. In this Review, we summarize major microenvironmental stresses in solid tumors, delineate membrane protein-mediated stress-adaptation mechanisms, and discuss clinically approved and emerging strategies targeting stress-responsive membrane proteins to enhance treatment efficacy and overcome therapeutic resistance.

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Fig. 1: Stress-responsive membrane proteins as execution nodes of tumor adaptation and malignant progression.
Fig. 2: Key stressors in the solid tumor microenvironment.
Fig. 3: Conceptual evolution of stress-responsive membrane protein research in cancer.
Fig. 4: Tumor microenvironment stress-driven transcription factor networks and membrane protein reprogramming.
Fig. 5: Stress-responsive membrane protein signaling in tumor survival, metabolic adaptation and immune evasion.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82573393, CW), the Research Foundation of Chinese Academy of Sciences (CW), and the Starting Fund from the University of Chinese Academy of Sciences (CW). All the artwork in this manuscript was created with BioRender.com.

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  1. These authors contributed equally: Xin He, Taoying Huang.

Authors and Affiliations

  1. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, China

    Xin He, Taoying Huang & Chengsheng Wu

  2. Medical School of Chinese PLA, Beijing, China

    Zhen Wang & Meng Xu

  3. Senior Department of Orthopedics, the Fourth Medical Centre, Chinese PLA General Hospital, Beijing, China

    Zhen Wang & Meng Xu

  4. Chapel Hill High School, Chapel Hill, NC, USA

    Fang Bu

  5. School of Pharmaceutical Sciences, Shanghai Jiao Tong University, Shanghai, China

    Xu Cao

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XH and TYH drafted the manuscript. ZW and FB performed literature search and edited the manuscript. XC, MX and CW performed literature search, critically reviewed and finalized the manuscript. All authors reviewed and approved the final manuscript.

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He, X., Huang, T., Wang, Z. et al. Stress-responsive membrane proteins as execution nodes of tumor cell adaptation to microenvironmental stress. Oncogene (2026). https://doi.org/10.1038/s41388-026-03768-y

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