Cancer immunotherapy, which primes the body's immune system to fight off tumors, has historically focused on harnessing T cells' natural ability 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 has been less effective against solid tumors, which tend to be "cold" environments, where anti-cancer immune responses are inactive and cancer-killing T cells are not recruited.
Biochemist Lingyin Li has been pioneering a new direction for immunotherapy, searching for drugs that would turn these "cold" environments "hot". Instead of stimulating T cells in the adaptive immune system, she focuses on harnessing cGAMP, one of the fast-acting inflammatory molecules in the innate immune system that serve as first responders to threats. Li discovered that tumors can evade detection (stay cold) by producing excess ENPP1 proteins that destroy cGAMP before it can trigger a broader immune response. With this knowledge of tumor behavior, she and her team developed STF-1623, a drug that inhibits ENPP1 and preserves cGAMP.
In a paper published September 5, 2025 in the journal Cell Reports Medicine , Li and her colleagues reveal the first evidence that a drug like STF-1623 can successfully activate the innate immune response to suppress tumors. It was effective in multiple mouse models of cancer, including breast, pancreatic, colorectal, and glioblastoma. No side effects were observed in mice, most likely because the drug only targets ENPP1 proteins highly concentrated in tumors and is quickly eliminated from the rest of the body.
"This pre-clinical study represents the first successful tumor specific targeting of an innate immune checkpoint, potentially offering a new approach for treating 'cold' tumors that don't respond to current immunotherapies," said Li ( @lingyinli.bsky.social ), an Arc Institute Core Investigator and Professor in the Biochemistry Department and the ChEM-H institute at Stanford University. "We first synthesized STF-1623 in 2016. This research builds on years of work understanding how ENPP1 helps cancer cells evade the innate immune system and how we can restore its function."
While the immune system is well known for protecting us against foreign bacteria and viruses, it also activates in response to internal threats. Whenever a cancer cell is genomically unstable, due to mutations, DNA can leak out of the nucleus or mitochondria. The surveillance protein cGAS detects the stray DNA, and produces cGAMP in response. The problem is that cancer cells disrupt this detection system by producing high levels of ENPP1, an enzyme that breaks down cGAMP before it can reach its target, STING. ENPP1 normally acts to prevent excessive inflammation, but in this case prevents cancer cells from being detected.
STF-1623 works by blocking ENPP1, allowing cGAMP to accumulate around cancer cells, enter surrounding immune cells, and trigger their STING pathways. As STING is activated, the alarm fully rings, and a larger and more coordinated immune response turns the tumor environment from "cold" to "hot", resulting in suppressed cancer growth.
STF-1623 is designed to stay on the surface of cancer cells, where ENPP1 is most abundantly found. By determining the atomic structure of STF-1623 bound to ENPP1, they revealed that STF-1623 fits perfectly into the active site of ENPP1 and coordinates with zinc ions crucial for the enzyme to function. STF-1623 differs from other drugs because of its long-term binding (over 24 hours) on ENPP1 active sites. This allows ENPP1 to inhibit cGAMP with increased efficacy while minimizing the likelihood of side effects.
While an innate immunity checkpoint inhibitor like STF-1623 is promising, it was most effective in combination with other cancer therapies in rodent models, and Li predicts that these drugs will work best in concert with a patient's treatment regimen. "Cancer is incredibly complex, and so, no single approach is likely to be sufficient for all patients," she said. "What we're trying to do here is help the body immunize itself against cancer by activating the innate immune system in the right place—at the tumor site."
This approach differs from direct STING agonists, which have shown limited success in early clinical trials. Rather than artificially setting off the immune system's most potent alarm, STF-1623 works by preserving naturally produced cGAMP in cancer cells, potentially resulting in a more controlled and targeted immune response.
With FDA approval to test STF-1623 in clinical trials, Li expects patient recruitment for phase I to start soon.
