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Within tumor cells, PAK4 promotes proliferation by activating phosphoinositide 3\u2010kinase (PI3K)\/AKT and mitogen\u2010activated protein kinase kinase (MEK)\/extracellular signal\u2010regulated kinase (ERK) signaling pathways. It enhances invasive and metastatic potential through cytoskeletal reorganization mediated by phosphorylation of effector proteins such as LIM domain kinase 1 (LIMK1)\/cofilin and actin nucleation\u2010promoting factor WASL (N\u2010WASP). Furthermore, PAK4 facilitates immune evasion by stabilizing programmed cell death ligand 1 (PD\u2010L1) and inhibiting pyroptosis. At the TME level, PAK4 is activated by hypoxia\u2010inducible factor 1\u2010alpha (HIF\u20101\u03b1), inflammatory cytokines, and extracellular matrix (ECM) stiffness. This activation reprograms the immune landscape, induces aberrant angiogenesis, and promotes metabolic acidosis via the Warburg effect, collectively fostering an immunosuppressive and therapy\u2010resistant niche. Small\u2010molecule PAK4 inhibitors (e.g., KPT\u20109274, PF\u20103758309, compound\n                    <jats:bold>55<\/jats:bold>\n                    ) and degraders (e.g., CPS\u2010021) effectively suppress tumor growth in preclinical models. Combining these agents with immune checkpoint blockade, chemotherapy, or radiotherapy reverses therapy resistance and reprograms the TME. Elevated PAK4 expression correlates significantly with poor patient prognosis and resistance to immunotherapy, positioning it as both a predictive biomarker and a promising therapeutic target. Elucidating the PAK4\u2010TME axis provides a mechanistic foundation for developing novel combinatorial strategies targeting the tumor microenvironment.\n                  <\/jats:p>","DOI":"10.1002\/med.70083","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T15:00:58Z","timestamp":1784818858000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["PAK4 in the Tumor Immune Microenvironment: Biological Functions, Regulatory Mechanisms, and Targeted Therapeutic Strategies"],"prefix":"10.1002","author":[{"given":"Yiming","family":"Wang","sequence":"first","affiliation":[{"name":"School of Clinical Pharmacy Shenyang Pharmaceutical University Shenyang China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wuxiyar","family":"Otkur","sequence":"additional","affiliation":[{"name":"School of Clinical Pharmacy Shenyang Pharmaceutical University Shenyang 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