The Major Histocompatibility Complex Class II molecules (MHC II) have the ability to present tumor antigens to CD4+ T cells, playing a critical role in initiating anti-cancer immunity. Recently, the discovery that MHC II is expressed on many atypical antigen-presenting cells (APCs) has exponentially increased interest in MHC II as a potential target for immunotherapy. Tumor immunotherapies targeting MHC II aim to enhance the sensitivity of tumors to CD4+ T-cell-mediated immune responses by increasing MHC II expression in tumor cells, especially in those traditionally classified as ”cold tumors”-tumors with insufficient T cell infiltration. In clinical studies, MHC II-based personalized vaccines, immune checkpoint blockade (ICB) therapy, and combination immunotherapies have yielded encouraging results.In this review, we describe the intricate cancer immunomodulatory network centered around on MHC II expression on both professional and atypical APCs, highlighting the challenges and opportunities for related immunotherapies. In addition, we analyze how the prediction of MHC II as tumor markers and their specific binding affinities can guide the development of precision medicine to address the unique complexity of each type of cancer.