# Biology of major folate transporters and STING signaling in cancer

> **NIH NIH R03** · WAYNE STATE UNIVERSITY · 2022 · $77,000

## Abstract

ABSTRACT
In mammalian cells, cyclic dinucleotides (CDNs) act as prominent danger signals that are sensed by the innate
immune sensor, stimulator of interferon genes (STING). Activation of STING elicits a signaling cascade that
culminates in the induction of type I interferons (IFNs) and various cytokines, thereby promoting a powerful
inflammatory response. Mammalian cells are able to produce their own CDNs, catalyzed by the cyclic guanosine
monophosphate–adenosine monophosphate (GMP-AMP) synthase (cGAS), which is activated by double-strand
DNAs to synthesize the eukaryotic CDN, 2′3′-cGAMP. Beyond intracellular CDNs, STING-activating CDNs can
originate from extracellular sources, such as therapeutic CDNs, cGAMP produced by tumor cells, and CDNs from
extracellular bacteria. The role of the cGAS-STING pathway in anti-tumor immunity supports the use of STING
agonists as cancer therapeutics. Inspired by the discovery that 2′3′-cGAMP activates human STING to initiate
robust downstream IFN signaling, STING-activating agents (mostly 2′3′-cGAMP analogues) were synthesized.
Direct pharmacologic activation of STING was shown to restrict tumor growth by a T cell-driven tumor
regression mechanism and to enhance immunogenicity. Administration of cGAMP in tumor-bearing mice also
potentiated the therapeutic effects of immune-checkpoint inhibitors and radiotherapy. Based on results with
CDN analogs in mice, two phase I clinical trials were initiated for the intra-tumoral delivery of STING agonists
(ADU-S100 and MK-1454) to solid tumors and lymphomas. Despite the impressive anti-tumor activity of STING
agonists in mice, initial results from clinical trials of such agonists have indicated a lower efficacy in humans.
The regulatory interplay among the import, export and degradation of CDNs remains an important and
interesting area for future research. Exogenous 2′3′-cGAMP and synthetic CDNs, including the investigational
new drug (IND) 2′3′-CDAS used in cancer immunotherapy, traverse the cell membrane through the reduced
folate carrier (RFC; SLC19A1) to activate STING in target cells, and the proton-coupled folate transporter (PCFT;
SLC46A1) enhances such response. RFC and PCFT are major facilitative transporters of folate in human tissues
and tumors. PCFT is unique from RFC in that it has an acidic rather than neutral pH optimum. RFC and PCFT
share substrates such as clinically used methotrexate and pemetrexed but also show their own unique substrate
specificities. Our group has studied RFC and PCFT structure, function and regulation extensively. In this R03
application, we explore the unique biology of RFC, as well as PCFT, and STING agonists in cancer, with a goal
of further understanding CDN uptake by these facilitative transporters and, by extension, improving
therapeutic applications. We propose in Aim 1 to study mechanisms of CDN uptake by RFC and PCFT under
physiological conditions. In Aim 2, we will study the molecular regulation of RFC in relation to CDN u...

## Key facts

- **NIH application ID:** 10435010
- **Project number:** 1R03CA259883-01A1
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** Zhanjun Hou
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $77,000
- **Award type:** 1
- **Project period:** 2022-04-05 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10435010

## Citation

> US National Institutes of Health, RePORTER application 10435010, Biology of major folate transporters and STING signaling in cancer (1R03CA259883-01A1). Retrieved via AI Analytics 2026-05-28 from https://api.ai-analytics.org/grant/nih/10435010. Licensed CC0.

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