Scientists Discover Cancer Protein That May Manipulate Macrophages to Help Tumors Evade T Cells

Have you ever wondered why certain cancers caused by the human papillomavirus (HPV) are so stubborn, even defying advanced immunotherapies? HPV-related cancers kill over 300,000 people worldwide each year, with cervical and head and neck cancers being particularly common. While HPV vaccines have been highly successful in preventing these diseases, treatment options for established HPV-positive tumors remain limited. In recent years, scientists have gradually realized that immune defection within the tumor microenvironment (TME) may be the key.

Recently, a study titled "HPV16 E6 and E7-expressing cancer cells suppress the antitumor immune response by upregulating KLF2-mediated IL-23 expression in macrophages" published in the Journal for ImmunoTherapy of Cancer reveals for the first time how HPV16 incites macrophages to release a cytokine called IL-23, thereby suppressing the immune system's attack on tumors.

This study aimed to answer a central question: Do the HPV16 E6/E7 oncoproteins suppress anti-tumor immune responses by upregulating IL-23 expression? The researchers employed a variety of experimental models, including the HPV16-positive mouse tumor cell line C3.43, B16 melanoma cells genetically engineered to express HPV16 E6/E7, and TCGA data derived from patient samples. Experimental subjects included immune cells (such as CD8+ T cells and macrophages), tumor-bearing mice, and the cultured RAW264.7 macrophage cell line. Techniques employed included flow cytometry, multi-omics single-cell RNA-seq ATAC sequencing, cytotoxicity assays, neutralizing antibody treatment, and CRISPR-Cas9 gene editing.

Figure 1. IL-23, a cytokine highly expressed in HPV+ cancer, reduces HPV16 E7 specific CD8 T-cell expansion and cytotoxicity. (Prins R, et al., 2025)

First, through bioinformatics analysis, the researchers discovered that IL-23 and IL-17 expression is significantly elevated in HPV+ tumors. Subsequently, in animal models, they confirmed that IL-23 directly inhibits the proliferation, cytokine secretion, and cytotoxicity of HPV-specific CD8+ T cells. The use of IL-23 neutralizing antibodies can increase the number of cytotoxic T cells within tumors, thereby slowing tumor growth. To investigate the upstream mechanisms of IL-23, the researchers used multi-omics sequencing to reveal that macrophages in the HPV+ tumor microenvironment highly express the transcription factor KLF2, which directly binds to and activates the enhancer region of the IL23A gene. Finally, they found that overexpressing KLF2 in vitro significantly increased IL-23 secretion in macrophages.

Thus, the HPV16 E6/E7 oncoproteins upregulate KLF2 in macrophages, prompting them to secrete large amounts of IL-23. IL-23, in turn, inhibits CD8+ T cell function, thereby enabling tumor immune evasion. Combining an IL-23 neutralizing antibody with a therapeutic vaccine targeting E6/E7 can improve anti-tumor efficacy and survival. This study not only reveals a novel pathway—the KLF2/IL-23 axis—through which HPV regulates the immune microenvironment, but also suggests a potentially transformative combination therapy strategy. Targeting IL-23 may enhance the efficacy of existing HPV vaccines, particularly for patients with advanced or treatment-resistant cancers.

The researchers point out that tumor "rebellion" is not without trace, and the scientific fightback begins by understanding their "secret signals." In the future, perhaps we can not only prevent HPV infection but also more intelligently dismantle the immune barriers it establishes.

Reference

Prins R, et al. HPV16 E6 and E7 expressing cancer cells suppress the antitumor immune response by upregulating KLF2-mediated IL-23 expression in macrophages. Journal for Immunotherapy of Cancer, 2025, 13(8): e011915.