New drug candidate STF 1623 prompts innate immunity in stable tumors

Most cancers immunotherapy, which primes the physique’s immune system to struggle off tumors, has traditionally centered on harnessing T cells’ pure means to acknowledge and assault most cancers cells. Whereas this method has saved the lives of sufferers with melanoma, in addition to sure lung cancers and blood cancers, it has been much less efficient in opposition to stable tumors, which are typically “chilly” environments, the place anti-cancer immune responses are inactive and cancer-killing T cells are usually not recruited.

Biochemist Lingyin Li has been pioneering a brand new path for immunotherapy, looking for medicine that may flip these “chilly” environments “scorching”. As a substitute of stimulating T cells within the adaptive immune system, she focuses on harnessing cGAMP, one of many fast-acting inflammatory molecules within the innate immune system that function first responders to threats. Li found that tumors can evade detection (keep chilly) by producing extra ENPP1 proteins that destroy cGAMP earlier than it may set off a broader immune response. With this information of tumor conduct, she and her group developed STF-1623, a drug that inhibits ENPP1 and preserves cGAMP. 

In a paper printed September 5, 2025 within the journal Cell Stories Drugs, Li and her colleagues reveal the primary proof {that a} drug like STF-1623 can efficiently activate the innate immune response to suppress tumors. It was efficient in a number of mouse fashions of most cancers, together with breast, pancreatic, colorectal, and glioblastoma. No unintended effects had been noticed in mice, probably as a result of the drug solely targets ENPP1 proteins extremely concentrated in tumors and is rapidly eradicated from the remainder of the physique.

This pre-clinical examine represents the primary profitable tumor particular focusing on of an innate immune checkpoint, probably providing a brand new method for treating ‘chilly’ tumors that do not reply to present immunotherapies. We first synthesized STF-1623 in 2016. This analysis builds on years of labor understanding how ENPP1 helps most cancers cells evade the innate immune system and the way we are able to restore its operate.”

Lingyin Li (@lingyinli.bsky.social), an Arc Institute Core Investigator and Professor within the Biochemistry Division and the ChEM-H institute at Stanford College

Whereas the immune system is well-known for shielding us in opposition to overseas micro organism and viruses, it additionally prompts in response to inside threats. Each time a most cancers cell is genomically unstable, on account of mutations, DNA can leak out of the nucleus or mitochondria. The surveillance protein cGAS detects the stray DNA, and produces cGAMP in response. The issue is that most cancers cells disrupt this detection system by producing excessive ranges of ENPP1, an enzyme that breaks down cGAMP earlier than it may attain its goal, STING. ENPP1 usually acts to stop extreme irritation, however on this case prevents most cancers cells from being detected.

STF-1623 works by blocking ENPP1, permitting cGAMP to build up round most cancers cells, enter surrounding immune cells, and set off their STING pathways. As STING is activated, the alarm absolutely rings, and a bigger and extra coordinated immune response turns the tumor setting from “chilly” to “scorching”, leading to suppressed most cancers progress. 

STF-1623 is designed to remain on the floor of most cancers cells, the place ENPP1 is most abundantly discovered. By figuring out the atomic construction of STF-1623 sure to ENPP1, they revealed that STF-1623 suits completely into the lively web site of ENPP1 and coordinates with zinc ions essential for the enzyme to operate. STF-1623 differs from different medicine due to its long-term binding (over 24 hours) on ENPP1 lively websites. This enables ENPP1 to inhibit cGAMP with elevated efficacy whereas minimizing the chance of unintended effects.

Whereas an innate immunity checkpoint inhibitor like STF-1623 is promising, it was handiest together with different most cancers therapies in rodent fashions, and Li predicts that these medicine will work greatest in live performance with a affected person’s remedy routine. “Most cancers is extremely advanced, and so, no single method is prone to be enough for all sufferers,” she stated. “What we’re attempting to do right here is assist the physique immunize itself in opposition to most cancers by activating the innate immune system in the best place-at the tumor web site.”

This method differs from direct STING agonists, which have proven restricted success in early scientific trials. Quite than artificially setting off the immune system’s most potent alarm, STF-1623 works by preserving naturally produced cGAMP in most cancers cells, probably leading to a extra managed and focused immune response.

With FDA approval to check STF-1623 in scientific trials, Li expects affected person recruitment for part I to start out quickly. 

The examine, “Innate immune checkpoint blockade with an ENPP1 inhibitor boosts intratumoral cGAMP to drive anti-cancer immunity,” was co-authored by Songnan Wang, Randolph Johnson, Jacqueline Carozza, Daniel Fernandez, Jan Scicinski, Neil Verity, Rachel Mardjuki, Xujun Cao, Yingjie Guo, Jacqueline Papkoff, Nigel Ray, and Lingyin Li. It’s now obtainable within the journal Cell Stories Drugs.

This work was supported by the Nationwide Institutes of Well being, the Arc Institute, and Angarus Therapeutics.