PAK4 in the Tumor Immune Microenvironment: Biological Functions, Regulatory Mechanisms, and Targeted Therapeutic...

p21-activated kinase 4 (PAK4), a critical effector of Ras homologous (Rho) GTP hydrolases (GTPases), promotes tumor progression and confers resistance to therapy by regulating malignant cellular phenotypes-such as proliferation, metastasis, and evasion of apoptosis-as well as by remodeling the tumor microenvironment (TME). Within tumor cells, PAK4 promotes proliferation by activating phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated 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-promoting factor WASL (N-WASP). Furthermore, PAK4 facilitates immune evasion by stabilizing programmed cell death ligand 1 (PD-L1) and inhibiting pyroptosis. At the TME level, PAK4 is activated by hypoxia-inducible factor 1-alpha (HIF-1α), 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-resistant niche. Small-molecule PAK4 inhibitors (e.g., KPT-9274, PF-3758309, compound 55) and degraders (e.g., CPS-021) 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-TME axis provides a mechanistic foundation for developing novel combinatorial strategies targeting the tumor microenvironment.