Chinese scientists have established a new technology platform that reveals how genetic mutations in tumors reshape the microenvironment and modulate immune responses, a discovery that could explain why modern cancer treatments often fail in patients whose cancers have spread.
The study, published in the journal Cell on Thursday, was jointly conducted by a Shanghai-based team from the Center for Excellence in Molecular Cell Science at the Chinese Academy of Sciences, in collaboration with teams from Shanghai Jiao Tong University, and Guangzhou Laboratory.
Using the new technology platform called CLIM-TIME (CRISPR-Laser-captured microdissection Integration Mapping of Tumor Immune Microenvironment), the researchers analyzed 391 common tumor suppressor genes to see how they reshape the tumor microenvironment — the biological neighborhood surrounding a tumor, and classified them into seven distinct subtypes.
The researchers found that the loss of certain tumor suppressor genes — genes that normally prevent cancer growth — triggers a massive buildup of collagen. This excess collagen makes the tumor structure so dense that it acts like a wall, preventing T cells — the body's natural "assassin" cells — from reaching and killing the cancer.
"It acts like a spider weaving a web. This web not only supports itself but also recruits and reshapes other normal cells from the body into accomplices that help shape this suppressive environment, blocking T cells' entry," said Wang Guangchuan, researcher at the Center for Excellence in Molecular Cell Science.
The team identified a specific molecule called LOXL2 as the architect of this barrier. In tests on mice, researchers found that by blocking LOXL2, they could dissolve the collagen wall. This allowed T cells to penetrate the tumor and significantly boosted the power of immunotherapy drugs.
We combined this with current CAR-T cell therapy. One major issue with CAR-T is that it can't enter solid tumors. When treating human tumors with CAR-T, if we use a small molecule to target this protein we've identified, it could significantly improve CAR-T treatment outcomes. Of course, when it comes to clinical application, we still need to evaluate its safety [and other indicators]," Wang said.
CAR-T is an immunotherapy involving the genetic engineering of a patient's T-cells to recognize and attack cancer cells.
Chinese scientists develop new technology to decode immunotherapy resistance in tumor microenvironment
