▲ EGFR-Targeted Ctx-ETAC Disrupts EV-Mediated Cancer-CAF Crosstalk to Reprogram the tumor microenvironment (TME). Ctx-ETAC suppresses EV secretion, disrupts cancer-CAF communication, and induces CAF and macrophage reprogramming, ultimately inhibiting tumor progression and metastasis through EV network collapse.
A research team led by Professor Yoosoo Yang of the Department of Integrative Biotechnology at Sungkyunkwan University (SKKU), in collaboration with a research team led by Dr. Man Kyu Shim of the Korea Institute of Science and Technology (KIST), has developed an innovative anticancer treatment platform that simultaneously targets cancer cells and the surrounding cells that support them, while blocking communication between the two.
Tumors do not grow through the activity of cancer cells alone. Cancer-associated fibroblasts (CAFs) and various immune cells gather around cancer cells, forming a complex community known as the tumor microenvironment. These cells communicate by exchanging extracellular vesicles (EVs), tiny packages that carry biological signals between cells. Through this communication, cancer cells become more aggressive, while surrounding cells help them spread to other organs and resist anticancer treatments. Conventional cancer therapies have primarily focused on directly attacking cancer cells, making it difficult to completely break this vicious cycle of support from surrounding cells.
To address this challenge, the research team focused on epidermal growth factor receptor (EGFR), a cell-surface receptor expressed on cancer cells and upregulated in activated CAFs. By targeting EGFR, the researchers developed a degrader-antibody conjugate (DAC) that combines an antibody capable of precisely targeting these cells with a drug that selectively degrades cyclooxygenase-2 (COX-2) inside the cells. Once this precision-targeted agent enters the two cell types, it suppresses the production and secretion of extracellular vesicles that carry signals between them.
As a result, the communication network through which cancer cells and surrounding stromal cells reinforce one another is disrupted. In cell-based experiments, the treatment reduced CAF activation, cancer cell migration, and tumor-promoting macrophage polarization. In an animal tumor model, it markedly suppressed tumor growth and remodeled the tumor microenvironment toward a more antitumor state. The study is particularly significant because it moves beyond conventional approaches that focus only on directly attacking cancer cells. By combining precision antibody targeting with targeted protein degradation, the new platform provides a strategy for disrupting the broader cellular ecosystem that supports tumor growth.
Professor Yoosoo Yang of the Department of Integrative Biotechnology said, “Cancer cells constantly communicate with surrounding cells to create an environment favorable to their own survival and growth. This study presents a new precision anticancer strategy that simultaneously targets cancer cells and their supporting cells while disrupting the harmful communication network between them, thereby affecting the tumor tissue as a whole.”
This research was supported by the Bio & Medical Technology Development Program funded by the Ministry of Science and ICT and the National Research Foundation of Korea. The findings were published in the Journal of the American Chemical Society (JACS), one of the world’s leading international journals in chemistry.
