The understanding of the relationship between immunological responses and cancers, especially those related to HPV, has allowed for the study and development of therapeutic vaccines against these neoplasias. There is a growing number of studies about the composition and influence of the tumor microenvironment (TME) in the progression or establishment of the most varied types of cancer. Hence, it has been possible to structure immunotherapy approaches based on therapeutic vaccines that are even more specific and directed to components of TME and the immune response associated with tumors. Among these components are dendritic cells (DCs), which are the main professional antigen-presenting cells (APCs) already studied in therapy strategies for HPV-related cancers. On the other hand, tumor-associated macrophages are also potential targets since the profile present in tumor infiltrates, M1 or M2, influences the prognosis of some types of cancer. These two cell types can be targets for therapy or immunomodulation. In this context, our review aims to provide an overview of immunotherapy strategies for HPV-positive tumors, such as cervical and head and neck cancers, pointing to TME immune cells as promising targets for these approaches. This review also explores the potential of immunotherapy in cancer treatment, including checkpoint inhibitors, cytokine immunotherapies, immunotherapy vaccines, and cell therapies. Furthermore, it highlights the importance of understanding the TME and its effect on the design and achievement of immunotherapeutic methods.

Breast cancer risk factors include lifestyle, genetic–hormonal influences, and viral infections. Human papillomavirus (HPV), known primarily as the etiological agent of cervical cancer, also appears active in breast carcinogenesis, as evidenced in our study of 56 patients from northeastern Brazil. We assessed the clinical and sociodemographic characteristics, correlating them with various breast cancer tumor types. HPV detection involved amplifying the L1 region, with viral load measured using the E2/E6 ratio and viral activity indicated by E5 oncogene expression. Predominantly, patients over 56 years of age with healthy lifestyles showed a high incidence of invasive ductal carcinoma and triple-negative breast cancer. HPV was detected in 35.7% of cases, mostly HPV16, which is associated with high viral loads (80 copies per cell) and significant E5 expression. These results hint at a possible link between HPV and breast carcinogenesis, necessitating further studies to explore this association and the underlying viral mechanisms.

Breast cancer is the most common neoplasm worldwide. Viral infections are involved with carcinogenesis, especially those caused by oncogenic Human Papillomavirus (HPV) genotypes. Despite the detection of HPV in breast carcinomas, the virus’s activity against this type of cancer remains controversial. HPV infection promotes remodeling of the host’s immune response, resulting in an immunosuppressive profile. This study assessed the individual role of HPV oncogenes in the cell line MDA-MB-231 transfected with the E5, E6, and E7 oncogenes and co-cultured with peripheral blood mononuclear cells. Immunophenotyping was conducted to evaluate immune system modulation. There was an increase in CD4⁺ T cell numbers when compared with non-transfected and transfected MDA-MB-231, especially in the Treg profile. Pro-inflammatory intracellular cytokines, such as IFN-γ, TNF-α, and IL-17, were impaired by transfected cells, and a decrease in the cytolytic activity of the CD8⁺ and CD56⁺ lymphocytes was observed in the presence of HPV oncogenes, mainly with E6 and E7. The E6 and E7 oncogenes decrease monocyte expression, activating the expected M1 profile. In the monocytes found, a pro-inflammatory role was observed according to the cytokines released in the supernatant. In conclusion, the MDA-MB-231 cell lineage transfected with HPV oncogenes can downregulate the number and function of lymphocytes and monocytes.

Lung cancer has the highest mortality rates worldwide, and Human Papillomavirus (HPV) has been associated with its carcinogenesis. In this study, HPV16 genes’ expressions were investigated in patient samples, along with the immunological response promoted by lymphocytes and monocytes in A549 cells transfected with HPV oncogenes and co-cultured with PBMC. An increase in the expression of E5 was observed in the patients’ samples. In the in vitro analysis, a decrease in the number of monocytes and cytotoxic cells was observed when co-stimulated by E6 and E7, and it promoted an increase in the Th2 profile. In contrast, the high proliferation of cytotoxic cells in A549 cells transfected with E5, associated with the high expression of costimulatory molecules in monocytes, suggests a low capacity of E5 to inhibit the presentation of antigens by antigen-presenting cells (APC) and a possible use of E5 in future therapeutic strategies against lung cancers associated with HPV.

Head and neck cancer (HNC) is the sixth most prevalent type of cancer worldwide and is associated with low five-year survival rates. Alcoholism and smoking are the main risk factors associated with the development of head and neck cancer (HNC). However, Human Papillomavirus (HPV) infection has been reported as a significant risk factor, particularly for the oropharyngeal subset. In these cases, patients with HPV-positive HNC exhibit a better clinical prognosis; however, resistance to chemotherapy has been frequently reported. The carcinogenic activity of HPV is related to the viral oncoproteins E5, E6, and E7. E5 has been associated with immune evasion mechanisms and modulation of the tumor microenvironment, which appears to be linked to the virus’s resistance to chemotherapeutic treatments. Here, we review the potential of HPV E5 in targeted therapy for HNC and discuss relevant data regarding the activity of this oncoprotein in head and neck carcinogenesis.