Cancer cells that detach from a primary tumor can remain dormant in the body, avoiding immune responses until conditions become favorable for forming new tumors elsewhere, a process called metastasis. Metastatic tumors, also known as stage 4 cancer, account for approximately 90% of cancer-related deaths. Understanding this process is a critical area of focus in cancer science.
Recent research conducted at Memorial Sloan Kettering Cancer Center (MSK) has demonstrated how metastatic cancer cells evade immune system elimination by altering their shape. MSK scientists found that cancer cells reduce their surface tension, which hinders immune cells from attaching to them. These findings, published on January 5 in Nature Cancer, describe a physical adaptation mechanism used by cancer cells for survival.
According to Joan Massagué, PhD, senior study author and Director of MSK's Sloan Kettering Institute, round cancer cells exhibit lower surface tension, making them more resistant to immune cell attacks. The study, led by Zhenghan Wang, PhD, a senior research scientist in the Massagué Lab, utilized cell cultures and mouse models of lung cancer. Dr. Wang stated that preventing cancer cells from adopting this soft state, or re-stiffening them, could assist the immune system in identifying and eliminating dormant metastases before new tumors develop.
Mechanism of Evasion
The research at MSK observed dormant metastatic lung cancer cells altering their physical shape using an atomic force microscope to study cellular mechanical properties. Cells change from an elongated, firm spindle shape to a softer, rounder form. This transition is mediated by the TGF-beta signal and the protein gelsolin. Gelsolin contributes to the breakdown of the cell's internal actin fiber scaffolding, decreasing cellular stiffness. The study indicated that softer, rounder cells are more difficult for natural killer cells and cytotoxic T cells of the immune system to engage.
The team also identified how TGF-beta signals influence cancer cell shape over time. Initial exposure to TGF-beta induces an epithelial-to-mesenchymal transition (EMT) in lung cancer cells, transforming fixed epithelial cells into mobile mesenchymal cells. During this phase, the lung cancer cells become elongated and stiffer. Prolonged exposure to TGF-beta, however, increases gelsolin production. This elevated gelsolin then disassembles and reorganizes the cells' fiber scaffolding, resulting in a softer, rounder cell shape.
Implications for Treatment
When researchers inhibited TGF-beta, reduced gelsolin, or otherwise prevented cells from softening, dormant cancer cells were more effectively eliminated by immune cells. This demonstrated TGF-beta's critical role in assisting dormant metastatic cells in evading immune responses over extended periods. The identification of this new mechanism of immune evasion suggests potential new therapeutic approaches. Dr. Massagué expressed optimism that ongoing research into dormant metastasis could ultimately lead to the prevention of metastatic cancer by facilitating the body's elimination of dormant cancer cells.
Study Details
The study's additional authors included Yassmin Elbanna, Inês Godet, Siting Gan, Lila Peters, George Lampe, Yanyan Chen, Joao Xavier, and Morgan Huse. Funding was provided by the National Institutes of Health / National Cancer Institute and grants from the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center at MSK, a Damon Runyon Quantitative Biology Fellowship, and postdoctoral fellowships from the Alan and Sandra Gerry Metastasis and Tumor Ecosystems Center. Dr. Massagué has reported ownership of company stock in Scholar Rock. The paper, titled "TGFβ induces an atypical EMT to evade immune mechanosurveillance in lung adenocarcinoma dormant metastasis," was published in Nature Cancer with DOI: 10.1038/s43018-025-01094-y.