The new candidate for drugs STF 1623 activates innate resistance in solid tumors

Cancer immunotherapy, which is subject to the body’s immune system to combat tumors, has historically focused on using the natural capacity of T cells to recognize and attack cancer cells. Although this approach saved the lives of patients with melanoma, as well as some lung cancers and blood cancers, it was less effective against lithium tumors, which are usually “cold” environments in which anti -cancer immune answers are not inactive, and T cells associated with cancer are not recruited.

Biochemist Lingyin Li is a pioneer of a new direction immunotherapyDrug search that would change these “cold” “hot” environment. Instead of stimulating T cells in an adaptive immune system, it focuses on the use of CGAMP, one of the fast -acting inflammatory molecules in the congenital immune system, which is the first to react to threats. Li discovered that tumors can avoid detection (remain cold), producing excess ENPP1 proteins that destroy CGAMP before they can start a wider immune response. Thanks to this knowledge about the behavior of the tumor, she and her team developed STF-1623, the drug inhibitory ENPP1 and retains CGAMP.

In an article published on September 5, 2025, in the magazine Li and her colleagues, they reveal the first evidence that a drug such as STF-1623 can successfully activate the innate immune response to tumor suppression. It was effective in many mouse cancer models, including breast, pancreas, large intestine and glioma. No side effects have been observed, most likely because the drug is only directed by ENPP1 proteins highly concentrated in tumors and are quickly eliminated from the rest of the body.

This pre -clinical test is the first successful innate management of congenital tumors of the immune control point, potentially offering a new approach to the treatment of “cold” tumors that do not respond to current immunotherapy. First, we synthesized the STF-1623 In 2016. The study is based on years of work understanding how ENPP1 helps cancer cells to avoid an innate immune system and how we can restore its function. “

Lingyin Li (@lingyinli.bsky.social), investigators and professor of the Arc Institute in the biochemistry department and the Chem-H Institute at the Stanford University University

While the immune system is known for protecting us against foreign bacteria and viruses, it is also activated in response to internal threats. Whenever the cancer cell is genomically unstable, due to DNA mutation, it can leak from the nucleus or mitochondria. The CGA supervision protein detects stray DNA and produces CGAMP in response. The problem is that cancer cells disturb this detection system, producing a high level of ENPP1, an enzyme that spreads CGAMP before they reach the goal, Sting. ENPP1 works normally to prevent excessive inflammationBut in this case, it prevents detection of cancer cells.

STF-1623 works by blocking ENPP1, enabling CGAMP to accumulate around cancer cells, enter the surrounding immune cells and triggering their path. As the Singing Alarm is activated, the larger and more coordinated immune response rotates the tumor environment from “cold” to “hot”, which causes a suppressed growth of cancer.

STF-1623 has been designed to stay on the surface of cancer cells, where ENPP1 is the most numerous. By determining the atomic structure of STF-1623 associated with ENPP1, they revealed that STF-1623 perfectly matches the active place of ENPP1 and coordinates with zinc ions key for the enzyme for functioning. STF-1623 differs from other drugs due to its long-term binding (over 24 hours) in active places ENPP1. This allows ENPP1 to brake CGAMP with increased effectiveness minimizing the likelihood of side effects.

While the innate inhibitor of the immunity control point, such as STF-1623, is promising, was the most effective in combination with other anti-cancer therapies in rodent models, and LI predicts that these drugs will work best in combination with the patient’s treatment scheme. “Cancer is extremely complex, so no single approach will probably be enough for all patients,” she said. “We try here to help the body resistance to cancer by activating the innate immune system in the right place in the place of the tumor.”

This approach differs from the direct agonists of the sting, which showed limited success in early clinical trials. Instead of artificial setting of the strongest alarm of the immune system, STF-1623 works by maintaining a naturally produced CGAMP in cancer cells, potentially causing a more controlled and targeted immune response.

Thanks to the confirmation by the FDA to test STF-1623 in LI clinical studies, LI expects that patients recruitment to the phase and will start soon.

Study: “The innate blockade of the immune point with the ENPP1 inhibitor strengthens the intratura CGAMP to drive anti -cancer resistance”, was co -authored by Sondnan Wang, Randolph Johnson, Jacqueline Carozza, Daniel Fernandez, Jan Scicinski, Neil Verity, Rachel Mardjuni Cao, Rachel Mardjuni Cao, Yingj, Yacquince, Jacquince, Jacquince, Papkoff, Nigel Ray and Lingyin Li. It is now available in the journal.

These works were supported by the National Institutes of Health, Arc Institute and Angarus Therapeutics.