Targeting KITENIN signaling in cancer progression and therapeutic resistance: mechanistic insights and future directions.

KITENIN (KAI1 C-terminal interacting tetraspanin) has emerged as a critical oncogenic mediator involved in tumor initiation, progression, metastasis, and therapeutic resistance. Initially identified through its interaction with the metastasis suppressor KAI1/CD82, KITENIN activates c-Jun N-terminal kinase (JNK) signaling and AP-1-dependent transcription, thereby driving epithelial-mesenchymal transition (EMT), cytoskeletal remodeling, and invasive behavior. Aberrant KITENIN expression has been reported in diverse solid tumors, including colorectal, gastric, hepatocellular carcinomas, and glioblastoma, where it correlates with aggressive phenotypes and poor prognosis. Preclinical studies show that genetic knockdown or pharmacological inhibition of KITENIN reduces metastatic potential and restores sensitivity to chemotherapy, underscoring its therapeutic relevance. Beyond metastasis, KITENIN contributes to cancer stemness, immune evasion, and resistance to conventional treatments, positioning it as a multifaceted regulator of tumor biology. Recent efforts to therapeutically target KITENIN include small molecules, natural compounds, and peptide-based inhibitors, though clinical translation remains in early stages. This review outlines the structural and mechanistic underpinnings of KITENIN-driven oncogenesis, evaluates its prognostic significance, and consolidates emerging evidence on KITENIN-targeted approaches. By highlighting current gaps and future directions, we propose that targeting the KITENIN axis holds promise for suppressing metastasis and improving outcomes in precision oncology.