Unraveling the Multimodal Oncogenic Network of KITENIN: From Metabolic Reprogramming and Microenvironment Remodeling to Targeted Interventions

ABSTRACT KAI1 C‐terminal interacting tetraspanin (KITENIN) is an emerging oncogenic regulator associated with tumorigenesis, metastasis, therapeutic resistance, and poor clinical outcomes. Mechanistically, KITENIN promotes tumor cell proliferation, migration, invasion, and epithelial–mesenchymal transition (EMT) by activating oncogenic pathways, including mitogen‐activated protein kinase/extracellular signal‐regulated kinase (MAPK/ERK) and activator protein 1 (AP1). Its interaction with the ErbB2 Receptor Tyrosine Kinase 4 (ErbB4) further promotes tumor invasion and metastatic progression. Beyond direct signaling, KITENIN contributes to tumor microenvironment remodeling and metabolic reprogramming via the c‐Myc/pyruvate kinase M2 (c‐Myc/PKM2) axis, supporting cancer cell survival and adaptation. Additionally, the Dishevelled/Protein kinase C delta (DVL/PKCδ) and KITENIN complex represents a novel signaling hub that integrates non‐canonical Wnt signaling with MAPK cascades, thereby triggering oncogenic signals and increasing tumor aggressiveness. In the context of therapeutic resistance, KITENIN confers temozolomide resistance by upregulating CD133 (prominin‐1) and SRY‐box transcription factor 2 (SOX2), highlighting its role in cancer stemness and chemoresistance. Therapeutic strategies, including siRNAs, microRNA‐124, peptides, and small molecules such as chrysophanol and emodin, have shown potential in suppressing KITENIN‐associated metastasis and resistance. This review synthesizes 2 decades of research on KITENIN as a multifaceted oncogenic scaffold, with particular emphasis on the integration of signaling, metabolic reprogramming, tumor‐microenvironment remodeling, cancer stemness, and therapeutic resistance. We further emphasize the context‐dependent nature of KITENIN signaling and distinguish KITENIN expression from functional pathway activity and tumor dependency, providing a framework for biomarker‐guided patient stratification and rational therapeutic combination in oncology.