Cellular Stress in the Tumor Microenvironment: Mechanisms and Therapeutic Opportunities

The tumor microenvironment imposes hypoxic, acidic, nutrient-poor, and mechanically stiff conditions that activate conserved cellular stress programs, including the HIF pathway, the unfolded protein response (IRE1α–XBP1, PERK–ATF4), the integrated stress response, and redox/ferroptosis control (NRF2–SLC7A11–GPX4). These stress cues remodel stromal and immune compartments—impairing dendritic cell cross-presentation, exhausting T/NK cells, skewing macrophages toward suppressive states, and promoting cancer-associated fibroblast secretion of pro-tumor cytokines—thereby shaping therapeutic resistance. We will also highlight implications for cellular immunotherapies: how hypoxia, acidosis, lactate/adenosine, and nutrient stress limit CAR T/NK trafficking and function, and engineering/combination strategies to overcome these barriers (e.g., hypoxia-responsive or “armored” CARs, A2A/TGF-β–resistant designs, metabolic rewiring, matrix/stiffness modulation, and pairing CARs with UPR/ISR or MCT inhibitors). This Research Topic will integrate mechanistic and translational studies that map stress signatures in spatially resolved TME niches; define how hypoxia, acidosis, nutrient and mechanical stress reprogram immune function; and test combinations that co-target stress pathways and immunotherapies. We welcome original research and reviews spanning model systems to patient datasets, with emphasis on biomarker development (hypoxia imaging, lactate/acidosis readouts, stress reporters), therapy timing/selection, and optimization of CAR T/NK efficacy in stressed TMEs. Topic editors: Mrinmoy Sarkar, Rani Ojha Source: https://www.frontiersin.org/research-topics/77134/cellular-stress-in-the-tumor-microenvironment-mechanisms-and-therapeutic-opportunities