HHLA2 overexpression promoted colorectal cancer growth by enhancing glycosylation and weakening the binding of HHLA2 to KIR3DL3

Colorectal cancer (CRC) ranks as the third most common cause of cancer-related fatalities globally, representing a significant public health challenge. The highest rates are reported in North America, Oceania, and Europe, particularly Eastern Europe, which may be related to “Westernized” lifestyles such as obesity and physical inactivity. In contrast, the incidence is relatively low in Asia, Africa, and South America. Colorectal cancer mortality is declining in many developed and emerging economies, linked to improved screening and treatment. However, in certain resource-limited countries like Mexico, Brazil, Romania, and Russia, mortality rates continue to rise. This suggests that despite advances in certain countries, colorectal cancer remains a serious global public health challenge and that a massive scale-up of targeted screening programs is needed to reduce its burden. HHLA2 is abundantly expressed in colorectal cancer tissues and inversely correlated with the presence of anti-tumor immune cells, indicating that it could have a dual function in both enhancing immune checkpoints and inhibiting immune responses. In addition, a change in the N-glycosylation pattern has been observed in colorectal cancer. It is closely related to the abnormal expression of glycosyltransferases. Further research on the mechanism of HHLA2 and N-glycosylation on the development and progression of colorectal cancer will help to better understand the role of these factors in colorectal cancer and provide new ideas for treatment.