# Immunotherapeutic targeting of MIF-dependent chaperone activity

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 2024 · $325,842

## Abstract

PROJECT SUMMARY
 “Immunotherapeutic targeting of MIF-dependent chaperone activity”
 Metabolic reprogramming that favors mitochondrial respiration plays an important role in controlling
differential gene expression patterns in myeloid lineage cells. Our recent findings have identified a novel protein
chaperone-dependent pathway that indirectly controls mitochondrial homeostasis and metabolic programming
that are needed to drive maximal intratumoral myeloid cell immune suppressive phenotypes. Our hypothesis
predicts that small molecule inhibition of this chaperone activity, carried out by the multifunctional cytokine MIF,
induces spontaneous Cu/Zn superoxide dismutase (SOD1) misfolding and aberrant mitochondrial binding
leading to metabolic reprogramming and subsequent phenotypic reversion of intratumoral myeloid cell immune
suppressive phenotypes into immune stimulatory phenotypes. Studies proposed in this application will: 1)
Delineate the mechanisms of action of 4-IPP-based MIF chaperone inhibitors in the context of MIF/SOD1-
dependent TAM/MDSC polarization; 2) Determine the relative contribution of hypoxia as a physiologic ER
stressor that exacerbates myeloid wt SOD1 misfolding in the context of MIF and 4-IPP, and 3) Evaluate the
therapeutic potential of lead MIF chaperone antagonists as individual and combinatorial modalities against
established metastatic melanoma.

## Key facts

- **NIH application ID:** 10818585
- **Project number:** 5R01CA279748-02
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **Principal Investigator:** ROBERT A MITCHELL
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $325,842
- **Award type:** 5
- **Project period:** 2023-04-01 → 2028-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10818585

## Citation

> US National Institutes of Health, RePORTER application 10818585, Immunotherapeutic targeting of MIF-dependent chaperone activity (5R01CA279748-02). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10818585. Licensed CC0.

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