Recent advancements in immunotherapy, particularly Chimeric antigen receptor (CAR)-T cell therapy and cancer vaccines, have significantly transformed the treatment landscape for leukemia. CAR-T cell therapy, initially promising in hematologic cancers, faces notable obstacles in solid tumors due to the complex and immunosuppressive tumor microenvironment. Challenges include the heterogeneous immune profiles of tumors, variability in antigen expression, difficulties in therapeutic delivery, T cell exhaustion, and reduced cytotoxic activity at the tumor site. Additionally, the physical barriers within tumors and the immunological camouflage used by cancer cells further complicate treatment efficacy. To overcome these hurdles, ongoing research explores the synergistic potential of combining CAR-T cell therapy with cancer vaccines and other therapeutic strategies such as checkpoint inhibitors and cytokine therapy. This review describes the various immunotherapeutic approaches targeting leukemia, emphasizing the roles and interplay of cancer vaccines and CAR-T cell therapy. In addition, by discussing how these therapies individually and collectively contribute to tumor regression, this article aims to highlight innovative treatment paradigms that could enhance clinical outcomes for leukemia patients. This integrative approach promises to pave the way for more effective and durable treatment strategies in the oncology field. These combined immunotherapeutic strategies hold great promise for achieving more complete and lasting remissions in leukemia patients. Future research should prioritize optimizing treatment sequencing, personalizing therapeutic combinations based on individual patient and tumor characteristics, and developing novel strategies to enhance T cell persistence and function within the tumor microenvironment. Ultimately, these efforts will advance the development of more effective and less toxic immunotherapeutic interventions, offering new hope for patients battling this challenging disease.