Biological Functions and Clinical Implications of CFLAR: From Cell Death Mechanisms to Therapeutic Targeting in Immune Regulation

Haiyang Zhang,1– 3 Xin Li,1– 3 Liangkang Lin1,4 1Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China; 2Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, People’s Republic of China; 3NHC Key Laboratory of Chronobiology, Sichuan University, Chengdu, People’s Republic of China; 4Department of Pediatrics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, People’s Republic of ChinaCorrespondence: Liangkang Lin, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of China, Tel/Fax +86 15361908128, Email [email protected]: Since its initial functional characterization in the late 1990s, CASP-8 and FADD-like apoptosis regulator (CFLAR) has been recognized as a crucial regulator of both apoptosis and immune responses. CFLAR inhibits caspase-8 activation by forming heterodimers with procaspase-8 at the death-inducing signaling complex (DISC), thereby preventing its proteolytic maturation. In addition to its role in cell death, CFLAR is integral to immune regulation, modulating NF-κB-dependent cytokine production (eg, IL-1β, TNF-α) and effector functions of T cells and macrophages. Recent studies underscore the pathological significance of dysregulated CFLAR expression in a variety of diseases, including cancers and inflammatory conditions. Within the tumor microenvironment, elevated CFLAR expression confers resistance to therapy, while in infectious and inflammatory diseases, its expression levels modulate the magnitude and direction of the immune response. This review provides an in-depth exploration of CFLAR’s structural and functional properties, focusing on its involvement in apoptosis, autophagy, and immune modulation. Moreover, we examine its translational potential as a therapeutic target, evidenced by ongoing preclinical studies targeting CFLAR isoforms in cancer immunotherapy. By synthesizing recent advances in CFLAR’s dual roles in cell death and immune surveillance, this review highlights actionable targets for overcoming therapy resistance and immune dysregulation.Keywords: CFLAR, apoptosis, autophagy, immunomodulation, signal path