Harnessing a key growth pathway to reprogram tumor-associated macrophages

By Wendy Bindeman

The local environment of a cancerous tumor is extremely complex. In addition to the cancer cells themselves, tumors contain many other cell types, including immune cells.  Macrophages, tissue-resident cells that take up and present antigens from their environments to help trigger an immune response, are one of the most abundant immune cells within tumors. However, tumor-associated macrophages frequently promote tumor progression. Understanding the signaling that causes TAMs to favor tumor growth is important for designing effective therapies to treat cancer.

Researchers in the lab of Vivian Weiss, assistant professor of pathology, microbiology, and immunology, recently published a review article in Cancer Research that describes the role of the Wnt pathway in TAMs and tumor biology. Wnt is a well-studied signaling pathway that regulates numerous cell behaviors, making it crucial for both typical development and cancer progression. First-author Megan Tigue, an M.D./Ph.D. student in the Program in Cancer Biology, focused on Wnt’s role in TAM polarization and promotion of tumor growth.

Wnt signaling within TAMs biases the cells toward a more tolerant, anti-inflammatory state, which allows for tumor growth and can facilitate invasion and metastasis. Additionally, Wnt ligands produced by TAMs can bind to cancer cells and, similarly, trigger pro-growth, pro-metastatic signaling. Recently, several groups have shown that Wnt signaling may help convert macrophages near tumors into TAMs, as well as attract the circulating version of macrophages—called monocytes—into the tumor.

Tigue’s analysis highlights both the complexities of Wnt’s role in cancer and the promise of Wnt inhibition as a treatment strategy, especially in combination with immunotherapies. Given the many components of the Wnt pathway and its crucial role in various normal biological processes, Wnt pathway inhibitors must be precisely designed and targeted to avoid unwanted side effects. However, inhibition of Wnt signaling in TAMs is an attractive strategy for cancer therapy, especially for patients whose tumors have substantial macrophage populations.

Tigue, M. L., Loberg, M. A., Goettel, J. A., Weiss, W. A., Lee, E., & Weiss, V. L. (2023). Wnt Signaling in the Phenotype and Function of Tumor-Associated Macrophages. Cancer research, 83(1), 3–11. doi.org/10.1158/0008-5472.CAN-22-1403.