Cancer immunotherapy, which promotes the body’s immune system to fight tumors, has historically focused on utilizing the natural capacity of T cells to recognize and attack cancer cells. While this approach has saved the lives of patients with melanoma, as well as certain lung cancers and blood cancers, it was less effective than solid tumors, which tend to be “cold” environments, where anti -cancer immunosuppression are inactive and inactive.
Biochemist Lingyin Li has pioneers in a new direction for immunotherapy, looking for medicines that will turn these “cold” hot “surroundings. Instead of stimulating T cells in the adaptive immune system, it focuses on utilizing CGAMP, one of the rapid action inflammatory molecules in the innate immune system that serve as first correspondents threats. Li has discovered that tumors can avoid detection (remain cold) producing excessive ENPP1 proteins that destroy CGAMP before causing a broader immune response. With this knowledge of tumor behavior, she and her team developed STF-1623, a drug that inhibits ENPP1 and maintains CGAMP.
In a document published on September 5, 2025 in the magazine The cell reference to medicineLee and her colleagues reveal the first proof that a drug such as STF-1623 can successfully activate the innate immune response to tumor suppressors. It was effective in multiple models of mouse cancer, including breast, pancreatic, colon and glioblastoma. No side effects were observed in mice, probably because the drug only targets ENPP1 proteins very concentrated in tumors and is quickly eliminated from the rest of the body.
This preclinical study represents the first successful specific volume targeting of an innate immune signal, possibly offering a new approach to the treatment of “cold” tumors that do not respond to current immunotherapy. We continued the STF-1623 in 2016. This research is based on years of understanding of the way ENPP1 helps cancer cells avoid the innate immune system and how we can restore its function. “
Lingyin Li (@lingyinli.bsky.Social), a key researcher at the ARC Institute and Professor in Biochemistry and the Chem-H Institute at Stanford University
While the immune system is known for our protection from foreign bacteria and viruses, it is also activated in response to internal threats. Whenever a cancer cell is genomically unstable because of mutations, DNA can be leaked from the core or mitochondria. CGAS monitoring protein detects stray DNA and produces CGamp in response. The problem is that cancer cells disturb this detection system, producing high levels ENPP1, an enzyme that breaks down the CGAMP before it can reach its target, sting. ENPP1 works normally to prevent excessive inflammation, but in this case it prevents the detection of cancer cells.
The STF-1623 operates by blocking ENPP1, allowing CGAMP to accumulate around the cancer cells, enter the immune system cells and activate sting streets. As the sting is activated, the alarm is fully typed and a larger and more coordinated immune response converts the tumor environment from “cold” to “hot”, resulting in suppressed cancer growth.
The STF-1623 is designed to remain on the surface of the cancer cells, where ENPP1 is more abundant. By determining the individual structure of STF-1623 ENPP1 committed, they revealed that STF-1623 fits perfectly into the active position of ENPP1 and coordinated with zinc ions that are critical to the enzyme to function. The STF-1623 differs from other drugs due to the long-term commitment (over 24 hours) in active ENPP1 positions. This allows ENPP1 to inhibit CGamp with increased efficiency, while minimizing the possibility of side effects.
While an innate inhibitor of immunity control points such as STF-1623 is very promising, it was more effective in combination with other rodent models cancer treatments, and Li predicts that these drugs will work better in consultation with the patient’s therapeutic regimen. “Cancer is incredibly complex and so no single approach is sufficient for all patients,” he said. “What we are trying to do here is to help the body to be immunized by cancer by activating the innate immune system in the right part of the tumor.”
This approach is different from the immediate Sting fighters, who have shown limited success in early clinical trials. Instead of artificially starting the most powerful alarm of the immune system, the STF-1623 operates by maintaining natural CGamp in cancer cells, possibly resulting in a more controlled and targeted immune response.
With the approval of the FDA for the STF-1623 test in clinical trials, LI expects to soon start recruiting patients for Phase I.
The study “Innate Immune Checkpoint Blockade with an ENPP1 inhibitor reinforces the inter -business CGamp to lead the immunity of objects, Rachel Mardjuki, Songnan Wang, Randolph Johnson, Jacqueline Carozza, Daniel Fernandez, Jan Jan Scicinski, Neil Verity Papkoff, Nigel Ray and Lingyin Li. The cell reference to medicine.
This project was supported by the National Institutes of Health, the ARC Institute and the Angarus Therapeutics.
Source:
Magazine report:
Wang, S., et al. (2025). The ENPP1 inhibitor with ultraviolet stay of the drug as an innate cancer treatment of immune cancer. The cell reference to medicine. doi.org/10.1016/j.xcrm.2025.102336
