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Copyright ©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Oncol. Jan 15, 2023; 15(1): 55-68
Published online Jan 15, 2023. doi: 10.4251/wjgo.v15.i1.55
Challenges and exploration for immunotherapies targeting cold colorectal cancer
Dan-Dan Li, Yuan-Ling Tang, Xin Wang
Dan-Dan Li, Yuan-Ling Tang, Xin Wang, Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan Province, China
Author contributions: Li DD analysed the data and wrote the paper; Tang YL collected the data; Wang X revised the paper.
Supported by National Natural Science Foundation of China, No. 82073338; Sichuan Science and Technology Support Project, No. 2021YFSY0039 and No. 22ZDYF0499; The 1·3·5 Project for Disciplines of Excellence-Clinical Research Incubation Project West China Hospital, Sichuan University, No. 2020HXFH002; and The 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University, No. ZYJC21059.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xin Wang, MD, PhD, Professor, Department of Abdominal Oncology/Radiation Oncology, Cancer Center, West China Hospital, Sichuan University, No. 37 Wainan Guoxue Lane, Wuhou District, Chengdu 610041, Sichuan Province, China. wangxin213@sina.com
Received: September 20, 2022
Peer-review started: September 20, 2022
First decision: October 14, 2022
Revised: October 28, 2022
Accepted: December 6, 2022
Article in press: December 6, 2022
Published online: January 15, 2023
Abstract

In recent years, immune checkpoint inhibitors (ICIs) have made significant breakthroughs in the treatment of various tumors, greatly improving clinical efficacy. As the fifth most common antitumor treatment strategy for patients with solid tumors after surgery, chemotherapy, radiotherapy and targeted therapy, the therapeutic response to ICIs largely depends on the number and spatial distribution of effector T cells that can effectively identify and kill tumor cells, features that are also important when distinguishing malignant tumors from “cold tumors” or “hot tumors”. At present, only a small proportion of colorectal cancer (CRC) patients with deficient mismatch repair (dMMR) or who are microsatellite instability-high (MSI-H) can benefit from ICI treatments because these patients have the characteristics of a “hot tumor”, with a high tumor mutational burden (TMB) and massive immune cell infiltration, making the tumor more easily recognized by the immune system. In contrast, a majority of CRC patients with proficient MMR (pMMR) or who are microsatellite stable (MSS) have a low TMB, lack immune cell infiltration, and have almost no response to immune monotherapy; thus, these tumors are “cold”. The greatest challenge today is how to improve the immunotherapy response of “cold tumor” patients. With the development of clinical research, immunotherapies combined with other treatment strategies (such as targeted therapy, chemotherapy, and radiotherapy) have now become potentially effective clinical strategies and research hotspots. Therefore, the question of how to promote the transformation of “cold tumors” to “hot tumors” and break through the bottleneck of immunotherapy for cold tumors in CRC patients urgently requires consideration. Only by developing an in-depth understanding of the immunotherapy mechanisms of cold CRCs can we screen out the immunotherapy-dominant groups and explore the most suitable treatment options for individuals to improve therapeutic efficacy.

Keywords: Colorectal cancer, Immune checkpoint inhibitors, Cold tumors, Immunotherapy mechanism, Combination therapy, Effector T cells

Core Tip: This review focuses on the potential mechanism of immunotherapy ineffectiveness in colorectal cancer patients with “cold tumors”, how to increase the infiltration of effector T cells at tumor sites by combination therapy strategies, how to transform “cold tumors” into “hot tumors” to expand the number of people benefiting from immunotherapy, and make recommendations on how to screen out immune-dominant populations in the future.