Abstract
Malignant tumors are a major threat to human health with the immune responses critically influenced by major histocompatibility complex (MHC) class I and II molecules. While MHC-I has been extensively studied for its role in tumor immunity, research on MHC-II, particularly MHC-II function within the tumor microenvironment, has lagged behind research on MHC-I. The expression and regulation of tumor-specific MHC-II (tsMHC-II) in tumor cells not only reflect the immunogenic landscape of the tumor microenvironment but also actively shape antitumor immune responses by modulating CD4(+) T cell recognition and activation. Expression of tsMHC-II is tightly controlled by intrinsic oncogenic signaling and extrinsic cytokine stimulation, positioning tsMHC-II as a key determinant of response to immunotherapy, including immune checkpoint blockade. Accordingly, tsMHC-II may serve as a predictive biomarker and a potential therapeutic target in tumor immunotherapy. This review highlights recent advances in the structure and function of MHC-II, the MHC-II regulatory mechanisms in tumors, and the emerging significance of MHC-II in guiding future immunotherapeutic strategies.