How Neuropeptides Like Substance P, CGRP, and VIP Influence Colorectal Cancer Through Immune Modulation | Research

The takeaway

Neuropeptides including substance P, CGRP, and vasoactive intestinal peptide play key roles in reshaping the immune environment of colorectal tumors, offering potential therapeutic targets.

3 key neuropeptides
Substance P, CGRP, and VIP actively modulate immune responses within colorectal tumors, influencing cancer progression

What the researchers found

The review systematically catalogs how three major neuropeptides influence colorectal cancer immunity:

1. **Substance P** — modulates immune cell recruitment and inflammatory responses in the tumor microenvironment

2. **Calcitonin gene-related peptide (CGRP)** — influences immune cell function and may affect how the tumor evades immune surveillance

3. **Vasoactive intestinal peptide (VIP)** — has immunomodulatory effects that can reshape the tumor's immune landscape

These neuropeptides, along with neurotransmitters and neurotrophic factors, form a complex neuroimmune axis that significantly impacts colorectal cancer progression and the tumor's ability to escape immune destruction.

Why it matters

Colorectal cancer is one of the most common cancers worldwide, and immunotherapy has shown limited success for many CRC patients. The neuroimmune axis represents an underexplored dimension of cancer biology. If neuropeptides are actively reshaping tumor immunity, then targeting or manipulating these peptides could enhance immunotherapy effectiveness or provide entirely new treatment strategies for CRC.

How the study worked

This is a comprehensive narrative review that systematically synthesizes published research on the neuroimmune axis in colorectal cancer. The authors categorized neuroregulatory mediators into neurotransmitters, neuropeptides, and neurotrophic factors, and evaluated their immunomodulatory effects in the context of CRC pathogenesis and tumor immunity remodeling.

What this study cannot tell us

As a review, this paper does not present new experimental data. Much of the evidence for neuropeptide effects on tumor immunity comes from in vitro and animal studies, with limited clinical validation in human CRC patients. The complex, context-dependent nature of neuropeptide signaling (sometimes pro-tumor, sometimes anti-tumor) makes therapeutic targeting challenging. The review also acknowledges that translational prospects face significant hurdles.

How to read the evidence

This is a comprehensive narrative review synthesizing evidence from multiple preclinical and early clinical studies. While it provides a thorough conceptual framework, the evidence for therapeutic targeting of neuropeptides in CRC is still at early research stages. No clinical trial data for neuropeptide-based CRC therapies is presented.

When this study was published

Published in 2025, this review reflects the current state of neuroimmune research in colorectal cancer and incorporates the latest understanding of neuropeptide roles in tumor biology.

The bigger picture

The concept that the nervous system influences cancer through neuropeptide signaling is a rapidly growing field. While most cancer immunotherapy research focuses on immune checkpoint proteins, this review highlights that neuropeptides represent a parallel immune regulatory system that is largely untapped therapeutically. The gut, with its dense nerve and immune cell networks, is a natural place where these interactions are most pronounced, making CRC a prime target for neuroimmune-based therapies.

Questions still open

Could blocking specific neuropeptides like substance P or CGRP in the tumor microenvironment enhance the effectiveness of immunotherapy for colorectal cancer?
Do patients with altered neuropeptide profiles in their tumors respond differently to existing cancer treatments?
Can VIP analogs be designed to selectively boost anti-tumor immunity while preserving its beneficial immunomodulatory effects elsewhere?

Common questions

What are neuropeptides and how do they relate to cancer?

Neuropeptides are small signaling molecules released by nerve cells. In the gut, which has an exceptionally dense network of nerves, these peptides — including substance P, CGRP, and VIP — can influence immune cell behavior. When a tumor develops in this environment, neuropeptides can reshape how immune cells respond to the cancer, either helping or hindering the body's ability to fight it.

Could targeting neuropeptides improve colorectal cancer treatment?

Potentially, yes. If specific neuropeptides are suppressing the immune system's ability to attack tumors, blocking those peptides could 'unleash' immune cells against the cancer. Conversely, peptides that boost anti-tumor immunity could be used therapeutically. However, this approach is still in early research stages and needs clinical validation.

Read the original research

Decoding the neuroimmune axis in colorectal cancer: From neural circuitry to therapeutic innovation.

Cytokine & growth factor reviews, 83, 3-17

View on PubMed ↗Publisher’s paper ↗

Citation

Li, Ying; Yang, Sheng-Ya; Zhang, Ying-Ru; Wang, Yan. (2025). Decoding the neuroimmune axis in colorectal cancer: From neural circuitry to therapeutic innovation.. Cytokine & growth factor reviews, 83, 3-17. https://doi.org/10.1016/j.cytogfr.2025.04.001