The article "CTLA-4: a moving target in immunotherapy" by Behzad Rowshanravan, Neil Halliday, and David M Sansom from the Institute of Immunity and Transplantation at University College London, provides an in-depth review of the CD28/CTLA-4 pathway, a critical regulator of T cell responses. CTLA-4, along with CD28, shares ligands CD80 and CD86, which mediate both stimulatory and inhibitory signals in T cells. The authors highlight the molecular and cellular biology of the CTLA-4 pathway, including the endocytic trafficking of CTLA-4 and its role in trans-endocytosis, a cell-extrinsic mechanism that reduces ligand availability for CD28. They also discuss the therapeutic implications of targeting the CTLA-4 pathway, particularly in cancer and autoimmune diseases, and the potential side effects of immune-related adverse events (irAEs) observed in clinical trials. The article emphasizes the importance of understanding the balance between CD28 and CTLA-4 in regulating T cell responses and the impact of CTLA-4 manipulation on Treg function.The article "CTLA-4: a moving target in immunotherapy" by Behzad Rowshanravan, Neil Halliday, and David M Sansom from the Institute of Immunity and Transplantation at University College London, provides an in-depth review of the CD28/CTLA-4 pathway, a critical regulator of T cell responses. CTLA-4, along with CD28, shares ligands CD80 and CD86, which mediate both stimulatory and inhibitory signals in T cells. The authors highlight the molecular and cellular biology of the CTLA-4 pathway, including the endocytic trafficking of CTLA-4 and its role in trans-endocytosis, a cell-extrinsic mechanism that reduces ligand availability for CD28. They also discuss the therapeutic implications of targeting the CTLA-4 pathway, particularly in cancer and autoimmune diseases, and the potential side effects of immune-related adverse events (irAEs) observed in clinical trials. The article emphasizes the importance of understanding the balance between CD28 and CTLA-4 in regulating T cell responses and the impact of CTLA-4 manipulation on Treg function.