Claudin proteins as emerging therapeutic targets for solid tumours

Claudins (CLDNs) are transmembrane proteins that contribute to the epithelial cell polarity and integrity of tight junctions in healthy tissues. CLDNs are frequently overexpressed across different solid tumours, and expression correlates with tumour subtype, grade and prognosis. Dysregulated CLDN expression modulates oncogenic signalling and contributes to tumour proliferation, epithelial-mesenchymal transition, stemness, fibrosis, immune modulation and therapeutic resistance. Owing to their frequent overexpression and functional role in cancer biology, CLDNs have emerged as attractive therapeutic targets. Their surface expression can be exploited to guide therapies into tumours. For example, a monoclonal antibody targeting the CLDN18.2 isoform has reached clinical approval, validating the potential of CLDN-directed approaches. Additional strategies such as antibody-drug conjugates, bispecific and trispecific antibodies and chimeric antigen receptor (CAR) T cells are in development for several CLDN family members. Targeting intracellular CLDN domains or their downstream signalling to disrupt their biological function may offer further promise. Here, we review the functional role of CLDN biology in solid tumours, summarize the clinical development of therapeutic approaches and discuss opportunities for biomarker-enriched patient selection. Collectively, we highlight CLDN targeting as a precision oncology approach relevant to multiple solid tumours.