Targeting RIPK1 to modulate cell death and tumour microenvironment in cancer therapy

Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) is crucial in regulating inflammation, apoptosis, and necroptosis. Accumulating evidence highlights RIPK1 as a promising therapeutic target for various human diseases, including neurodegenerative disorders, autoimmune diseases, and cancer. In tumour cells, RIPK1 suppresses immunogenic cell death, promotes an immunosuppressive tumour microenvironment, which facilitates immune evasion, metastatic progression, and therapeutic resistance, contributing to an immunologically cold tumour phenotype. Therefore, targeting RIPK1 represents a promising therapeutic approach to overcome immune checkpoint blockade resistance and convert tumours into an immunologically hot phenotype. In this review, we summarise the biological functions of RIPK1 and elaborate on its roles in cancer progression in terms of the tumour immune microenvironment, tumour metastasis, and chemoresistance. Furthermore, we enumerate several identified RIPK1-targeted inhibitors with potential for cancer therapy. Although RIPK1 has been proposed as a potential anticancer target, there are still great opportunities and challenges that require further investigation.