SLC13A3 in tumor resistance to immunotherapy

Immune checkpoint blockade (ICB) therapies have transformed the landscape of cancer treatment by unleashing cytotoxic T cell responses against tumors. However, a large proportion of patients remain unresponsive, particularly those with “cold” tumors characterized by low pre-existing T cell infiltration and diminished immunogenicity. A key determinant of tumor immunogenicity is the expression of major histocompatibility complex class I (MHC-I) molecules, which are essential for antigen presentation and CD8 T cell-mediated tumor recognition. MHC-I loss is a well-established mechanism of immune evasion, observed in more than half of all cancer patients across multiple tumor types. Strategies to restore MHC-I expression therefore represent an urgent therapeutic need. Our recent studies identify a novel immunosuppressive mechanism involving the tumor cell transporter SLC13A3, which imports the metabolite itaconate from the tumor microenvironment (TME) and promotes tumor resistance to ferroptosis, aligned with low tumor immunogenicity. However, the precise mechanism by which itaconate and SLC13A3 contribute to reduced tumor immunogenicity remains unclear. Preliminary data show that itaconate suppresses IFNγ-induced MHC-I expression in tumor cells, suggesting that the itaconate-SLC13A3 axis functions as a metabolic checkpoint that regulates tumor immunogenicity. We hypothesize that itaconate suppresses MHC-I expression through two complementary mechanisms: (1) Itaconate covalently modifies (alkylates) STAT1, thereby altering IFNγ signal transduction and transcription of MHC-I-related genes; and (2) itaconate alkylates p62, a scaffold protein that interacts with Keap1, leading to activation of the Nrf2 pathway, limiting interferon signaling, and promoting ferroptosis resistance. Together, these mechanisms position the itaconate-SLC13A3 axis as a key regulator of tumor immunogenicity. To test this central hypothesis, we propose two specific aims: Aim 1: Define the role and molecular mechanisms of the itaconate-SLC13A3 axis in regulating tumor MHC-I expression. We will integrate bioinformatics, metabolomics, proteomics, and immunologic approaches to dissect the regulatory effects of itaconate on STAT1 and p62 and their downstream consequences on MHC-I, immune signaling, and tumor cell killing. Aim 2: Develop and evaluate therapeutic agents targeting SLC13A3 to overcome ICB resistance. We have generated a panel of monoclonal antibodies (mAbs) that bind extracellular domains of human and mouse SLC13A3. We will evaluate these mAbs for their ability to inhibit itaconate transport and restore MHC-I expression. In parallel, we will develop bispecific antibodies targeting SLC13A3 and PD-L1 or tumor surface ubiquitin ligases to enhance therapeutic efficacy and promote targeted degradation of SLC13A3. This proposal will uncover novel metabolic mechanisms by which tumors evade immune surveillance and will establish proof-of-concept for targeting the itaconate- SLC13A3 axis as a strategy to restore tumor immunogenicity and overcome ICB resistance. Project Number: 1R01CA299259-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Heng Lin (+1 co-PI) | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $544,868 | Activity Code: R01 | Study Section: Therapeutic Immune Regulation Study Section[TIR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11363611