Considering what was said about Heat Shock Proteins (HSPs) role in the presentation of tumor antigens, today, before using tumor cell extracts as antigens in vaccine preparation, researchers try to increase the efficiency of antigen presentation by APCs via inducing these proteins; however, since different cell lines express different amounts of HSPs under the influence of different temperatures and different incubation times, discussing the optimal temperature and post-temperature incubation for cancer cell lines that may cause the next stages of the production of cancer cell vaccines, will be very useful. Through systematic search in PubMed/Medline using ("Tumor"[Title/Abstract] OR "Cancer"[Title/Abstract] OR "Neoplasm"[Title/Abstract]) AND ("vaccine"[Title/Abstract] OR "vaccination"[Title/Abstract]) AND ("heat shock protein"[Title/Abstract] OR "HSP"[Title/Abstract]) from 1980 to 2025. Overall, 18 articles were selected from a total of 414. The results of clinical trials confirm the use of HSPs in cancer vaccine therapy. A total of 18 studies, including 1,116 cases with different forms of cancer, were reviewed. These studies spanned different trial phases (I–III) and utilized a range of HSP-based vaccines to evaluate their safety, immunogenicity, and efficacy. HSPPC-96 was the most commonly investigated vaccine. These results indicate that the specific tumor-specific effects of the HSPs' immune response, including cluster of differentiation 4 (CD4+), interferon gamma (IFN-γ), and CD8+, lead to a much stronger vaccination. These outcomes underscore the complexity of the tumor microenvironment and the necessity for tailored approaches to maximize therapeutic success. Advances in vaccine formulation, production, and combination therapies offer promising pathways to address these challenges.