# Role of immune regulation in colorectal cancer chemotherapeutic response

> **NIH NIH R01** · YALE UNIVERSITY · 2024 · $465,478

## Abstract

PROJECT SUMMARY
 Colorectal cancer (CRC) is the second leading cause of cancer death in the United States.
Conventional cytotoxic chemotherapy remains a key treatment modality for advanced-stage disease
prolonging overall survival, yet clinical responses vary substantially among patients. The most widely
used chemotherapy regimens for CRC are formulated with 5-fluorouracil (5-FU) as the backbone. The
effects of 5-FU have been extensively studied in vitro and in immunodeficient mice. However, what
underlies 5-FU’s anti-cancer efficacy in vivo in immunocompetent settings remains poorly understood,
the understanding of which will be critical for devising more effective and/or less toxic strategies against
CRC. It is well recognized that cancer-cell-intrinsic sensitivity to 5-FU in vitro can partially explain
responsiveness to 5-FU in vivo, with the underlying model that for intrinsically sensitive cancers, 5-FU
reduces tumor burden primarily through direct cytotoxicity on cancer cells. However, whether this
conventional model is accurate in immunocompetent hosts is not clear. Based on preliminary data, we
propose to test a revised model for how 5-FU is effective in immunocompetent settings: 5-FU-induced
reduction of tumor-burden requires two components, cancer cells’ intrinsic sensitivity to the drug to
prime the response and a distinct requirement for immune modulation to play a major role in reducing
tumor burden. Lacking either component will reduce 5-FU efficacy in vivo. We will test this revised
model through three complementary aims. In the first aim, we will test the dual requirements of cancer-
cell-intrinsic chemosensitivity and immune modulation for effective response to 5-FU in vivo. In the
second aim, we will determine the molecular and cellular basis of the immune modulation that reduces
tumor burden. In the third aim, we will investigate the relationship between the cGAS-STING pathway
and chemotherapy response of human colon tumors. Findings from these studies have the potential
to transform our understanding of how 5-FU works in vivo and build a bridge between 5-FU
effectiveness and anti-tumor immunity. This project also has the potential to unveil new prognostic and
therapeutic strategies for CRC patients. Given that 5-FU is also used in other malignancies (e.g.,
pancreas, gastric, biliary, small intestinal, breast, head and neck), our studies have treatment
implications well beyond CRC.

## Key facts

- **NIH application ID:** 10916319
- **Project number:** 5R01CA256530-04
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jun Lu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $465,478
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10916319

## Citation

> US National Institutes of Health, RePORTER application 10916319, Role of immune regulation in colorectal cancer chemotherapeutic response (5R01CA256530-04). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10916319. Licensed CC0.

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