Cancer immunotherapy has changed the way many cancers are treated. Yet only a proportion of patients achieve strong and durable clinical benefit. For this reason, researchers are looking beyond the first wave of immune checkpoint targets and focusing on signals that help T cells stay active for longer.

In the fieldof immunotherapy, IL-4Rα serves as the shared receptor for the two key inflammatory pathways, IL-4 and IL-13, playing a central regulatory role in type 2 immune responses. It is a significant therapeutic target in areas such as asthma and atopic dermatitis. The targeted drug Dupilumab achieved global sales close to $14.1 billion in 2024, demonstrating immense commercial potential. With the remarkable commercial success of drugs like Dupilumab and the continuous expansion of their indications from dermatological and respiratory diseases to the tumor microenvironment, IL-4Rα has emerged as another star target, alongside PD-1, possessing high clinical translation value and broad market prospects.

CTLA-4 (CD152)? holds the distinction of being the first immune checkpoint inhibitor? pathway sanctioned by the FDA? for oncology? applications. Following its discovery in the 1990s, the development of Ipilimumab (Yervoy?)? established CTLA-4 as a critical target in tumor immune evasion. Currently, CTLA-4 targeted therapies are a vital component in the clinical management of refractory solid tumors, including melanoma? and renal cancer.

In the adaptive immune response, T cell functional activation relies on a critical two-signal regulatory mechanism. T cell receptor (TCR) recognition of the MHC-antigen peptide complex on the surface of antigen-presenting cells (APCs) provides the first signal. The co-stimulatory receptor CD28 binding to its ligands B7.1 (CD80) and B7.2 (CD86) on APCs provides the essential second signal. Together, these signals drive full T cell activation, clonal proliferation, and effector differentiation. The CD28 signal drives T cell clonal expansion, effector differentiation (e.g., IL-2 secretion), and metabolic reprogramming. Its precise regulation has become a central target in tumor immunotherapy and autoimmune disease intervention.

Cancer does not grow and spread on its own. It depends on signals that tell tumor cells to survive, divide, move, and resist treatment. One of the most important of these signaling systems is the HGF/MET axis.