Rethinking Cancer Immunotherapy #
Cancer immunotherapy has largely focused on stimulating T cells in the adaptive immune system. While this approach has saved patients with melanoma, lung cancers, and some blood cancers, it has been less effective against solid tumors, which are often “cold” environments that suppress immune responses.
Stanford biochemist Lingyin Li has taken a different approach, looking to the innate immune system for answers. Her research focuses on cGAMP, an inflammatory signaling molecule that normally alerts immune cells to cancer. Tumors, however, escape detection by producing excess ENPP1 proteins, which destroy cGAMP before it can activate immune defenses.
To counter this, Li and her team developed STF-1623, a first-in-class drug that inhibits ENPP1, preserves cGAMP, and activates the STING pathway to restore innate immune responses.
Breakthrough Findings Published in Cell Reports Medicine #
In a study published on September 5, 2025, in Cell Reports Medicine, Li’s team reported that STF-1623 successfully activated innate immunity in multiple mouse models of cancer, including:
- Breast cancer
- Pancreatic cancer
- Colorectal cancer
- Glioblastoma
The treatment suppressed tumor growth with no observed side effects, likely because STF-1623 only targets ENPP1 concentrated on tumor cells and clears rapidly from the rest of the body.
“This pre-clinical study represents the first successful tumor-specific targeting of an innate immune checkpoint,” said Li. “It builds on years of work understanding how ENPP1 helps cancer cells evade detection and how we can restore the body’s immune response.”
How STF-1623 Works #
The immune system normally detects genomic instability in cancer cells. When DNA leaks outside the nucleus or mitochondria, the cGAS protein detects it and produces cGAMP, which should activate the STING pathway. Tumors disrupt this process by producing ENPP1 to break down cGAMP.
STF-1623’s mechanism of action:
- Blocks ENPP1, preventing breakdown of cGAMP.
- Preserves cGAMP near tumor cells.
- Activates STING pathways in surrounding immune cells.
- Transforms tumors from “cold” to “hot”, enabling a coordinated anti-cancer immune response.
Structural studies revealed that STF-1623 binds tightly to ENPP1’s active site and interacts with zinc ions critical for its function. Unlike other drugs, STF-1623 remains bound for over 24 hours, giving it lasting efficacy with minimal off-target effects.
Potential for Combination Therapies #
While promising on its own, STF-1623 was most effective when used in combination with other cancer therapies in rodent models.
“Cancer is incredibly complex, and no single approach is likely to be sufficient for all patients,” Li said. “Our goal is to help the body immunize itself against cancer by activating innate immunity directly at the tumor site.”
This approach differs from direct STING agonists, which often trigger excessive immune responses and have shown limited success in clinical trials. By preserving the body’s naturally produced cGAMP, STF-1623 may provide a more controlled and tumor-specific immune activation.
Looking Ahead #
The FDA has approved clinical trials for STF-1623, and phase I patient recruitment is expected to begin soon.
The study, “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.
This work was supported by the National Institutes of Health, the Arc Institute, and Angarus Therapeutics.
Conclusion #
STF-1623 represents a major step forward in cancer immunotherapy. By targeting innate immune checkpoints rather than adaptive immunity, this new approach could finally unlock effective treatments for solid tumors that remain resistant to current therapies.
If clinical trials confirm its promise, STF-1623 may open a new frontier in the fight against cancer.