{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMICA, a stress‐inducible MHC class I chain–related molecule, is expressed on transformed, infected, or otherwise “distressed” cells and functions as a potent ligand for the activating immunoreceptor NKG2D present on natural killer, γδ, and CD8+ T cells. Engagement of MICA by NKG2D triggers cell‐mediated cytotoxicity and costimulates adaptive responses, thereby playing a key role in tumor immune surveillance and anti–microbial defense."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nParadoxically, while cell‐surface MICA stimulates anti–tumor effector functions, many tumors and virally infected cells employ proteolytic mechanisms to shed MICA from their surfaces. This release of soluble MICA leads to down‐regulation and internalization of NKG2D on effector cells, thereby impairing antigen‐specific and innate cytotoxic responses and contributing to immune evasion. In many instances, this proteolytic shedding is mediated by metalloproteinases (including ADAM10 and ADAM17) and by enzymes such as ERp5 that promote cleavage of membrane–proximal domains of MICA."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its immunostimulatory role, the regulation and expression pattern of MICA bear significant clinical and pathophysiological implications. Studies have documented MICA expression on a broad range of tumors—including leukemias, hepatocellular and ovarian carcinomas, and colorectal cancers—and its levels, as well as the abundance of its soluble form, can correlate with disease stage, prognosis, and immune evasion. Transcriptional regulation of the MICA gene is influenced by cellular stress signals and viral products, while its polymorphic nature has been linked to susceptibility not only to malignancies but also to inflammatory and autoimmune disorders such as Crohn’s disease and type 1 diabetes. Moreover, MICA’s functional balance with inhibitory ligands (for example, HLA‐G1) or its modulation by oncogenes (such as BCR/ABL) and viral immune evasion proteins (e.g. adenovirus E3/19K) further underscore its dynamic role in shaping immune responses. These diverse findings—from dendritic cell–mediated induction of MICA to its altered cell–surface expression during hypoxic conditions and after viral infection—highlight the importance of MICA as both a mediator of cytotoxic lymphocyte activation and as a target for tumor and pathogen countermeasures."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Veronika Groh, Jennifer Wu, Cassian Yee, et al. 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