# Mining the microbiome for immunomodulatory microproteins

> **NIH CA R01** · STANFORD UNIVERSITY · 2026 · $640,554

## Abstract

PROJECT ABSTRACT
Cancer immunotherapy, when effective, is lifesaving. Unfortunately, 15-50% of individuals will not respond to
therapy; therefore, efforts to ‘flip the switch’ and turn these ‘non-responders’ into ‘responders’ are critical and
urgent. Encouragingly, phenomenological studies in humans and preclinical studies in mice have demonstrated
that the gut microbiome is associated with cancer immunotherapy response. However, the exact mechanisms
that drive microbiome-based changes in immunotherapy response are not known. This project will elucidate how
microbial microproteins modulate macrophage function, a critical coordinator of tumor immune response. The
central hypothesis of this proposal is that specific gut microbes express microproteins that directly
modulate macrophages, thus leading to immunomodulation of cancer. Previous work seeking to
deconvolute the signaling interface between microbes and immune cells has done so by: (i) carrying out limited-
throughput, arrayed screens, (ii) focusing on microbial small molecule metabolites and (iii) focusing on T-cells.
Here, we propose to address many gaps left by these approaches. Namely, we will (i) carry out two orthogonal
high-throughput screens (peptide-display polarization assay, Perturb-seq) of 1,000s-10,000s of microbial
macromolecules in pooled screens (technical innovation), (ii) focus on proteins, especially an understudied class
of microproteins we recently discovered and have now annotated in microbial genomes (conceptual innovation),
and (iii) moving one step up in the immunological ‘cascade’ by focusing on macrophages (conceptual innovation).
Our strong preliminary data have identified two novel macrophage-modulating microbial proteins that we will
mechanistically study in Aim 1, and we have also developed and validated a powerful peptide display system
that will be expanded in Aim 2. Building upon these preliminary data, we will: (Aim 1) determine the detailed
molecular mechanisms, including targ

## Key facts

- **NIH application ID:** 11321675
- **Project number:** 5R01CA301727-02
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** MICHAEL C BASSIK; Ami Siddharth Bhatt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $640,554
- **Award type:** 5
- **Project period:** 2025-05-01T00:00:00 → 2030-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11321675

## Citation

> US National Institutes of Health, RePORTER application 11321675, Mining the microbiome for immunomodulatory microproteins (5R01CA301727-02). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11321675. Licensed CC0.

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