# Tunneling Nanotube Inhibitors for Cancer Immunotherapy

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $620,466

## Abstract

ABSTRACT
In a recent study published in Nature Nanotechnology, we demonstrated that cancer cells form physical
nanoscales tentacles (nanotubes) to connect with and harvest mitochondria from immune cells. Such
mitochondria hijacking metabolically depleted the immune cells and augmented the cancer cells. These
findings have significant implications as it emerges as a novel mechanism of immune evasion by cancer
cells, which can limit the efficacy of immune checkpoint inhibitors. Here we propose to develop next-
generation immunotherapies that can perturb this novel immune evasion phenomenon. We are specifically
developing novel small molecule inhibitors of the exocyst complex, which we have implicated in the above
phenomenon. Our preliminary results show that such small molecules can exert a powerful antitumor
efficacy, augment classical immune checkpoint inhibitors and display an excellent safety profile. In Aim 1.
We will synthesize and characterize exocyst inhibitors in vitro to test the hypothesis that rationally designed
small molecule inhibitors of the exocyst complex can inhibit nanotube assembly. In Aim. 2. We will establish
the safety pharmacology of exocyst inhibitors in vivo. In Aim 3, we will test the hypothesis that exocyst
inhibitors can improve antitumor outcomes with immune checkpoint inhibitors. Achieving these aims will lead
to fundamental insights into a new mechanism of cancer-immune cell communication. Our preliminary
results indicate exocyst inhibitors can emerge as a new class of immunotherapy.

## Key facts

- **NIH application ID:** 10890886
- **Project number:** 5R01CA276525-02
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** Shiladitya Sengupta
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,466
- **Award type:** 5
- **Project period:** 2023-07-19 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890886

## Citation

> US National Institutes of Health, RePORTER application 10890886, Tunneling Nanotube Inhibitors for Cancer Immunotherapy (5R01CA276525-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10890886. Licensed CC0.

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