Colorectal cancer (CRC) is the third most common cancer globally and the second leading cause of cancer death. Within the tumor, a complex ecosystem of cells surrounds and interacts with cancer cells - this is called the tumor microenvironment (TME).
Among the most influential residents of this ecosystem are tumor-associated macrophages (TAMs) - immune cells that have been hijacked by the tumor. Rather than fighting cancer, TAMs often promote it by helping tumors grow, invade surrounding tissue, escape immune detection, and develop new blood vessels.
Over the past decade, research on TAMs in CRC has expanded rapidly. This study used bibliometric analysis - a quantitative approach to mapping scientific literature - to chart where the field has been and where it is heading.
The researchers searched the Web of Science Core Collection - one of the most comprehensive scientific databases - using specific search terms for colorectal cancer and macrophages. The search captured all publications from the database's inception through April 2025.
After filtering out reviews, conference abstracts, and letters, 2,861 original research articles met the inclusion criteria. Two independent researchers reviewed the publications to ensure quality.
Two specialized software tools were used for visualization and analysis: VOSviewer mapped collaboration networks between countries, institutions, and journals, while CiteSpace identified keyword clusters, research hotspots, and how the field has evolved over time.
The analysis revealed a consistent and accelerating growth in CRC TAMs research since 2018. The peak year was 2024, with 383 publications - more than 13% of all papers in the entire history of the field published in a single year. The pace shows no sign of slowing.
China leads the world in publication output with 1,381 papers (48% of all publications), followed by the United States (557 papers) and Japan (220 papers). However, the United States maintains the most international collaborations, suggesting China has room to grow its global scientific partnerships.
At the institutional level, Sun Yat-sen University is the most productive, with 130 published papers, ahead of Zhejiang University (89 papers) and Fudan University (81 papers). A total of 3,642 institutions worldwide have contributed to this research area.
Keyword analysis identified five major research clusters that define the field: (1) CRC biology including basic tumor characteristics; (2) TAM characterization covering how macrophages function; (3) patient survival outcomes; (4) disease progression mechanisms including invasion and metastasis; and (5) metastatic processes and therapeutic strategies.
Early research (2007-2015) focused on how macrophages interact with chemotherapy drugs like irinotecan and oxaliplatin. From 2016 onward, emphasis shifted to TAM identification and tumor invasion. The most recent period (2019-2025) has centered on the broader tumor immune microenvironment and the role of gut microbiota.
One consistent finding across the timeline: irinotecan - a chemotherapy drug - has been repeatedly highlighted as especially relevant to macrophage biology in CRC, suggesting it may have immunomodulatory effects beyond its direct cancer-killing action.
The bibliometric analysis identified four key directions likely to dominate future research. First, single-cell RNA sequencing is being used to map TAM diversity at unprecedented resolution, revealing that macrophages in tumors are not a uniform population but a complex mix of subtypes with distinct roles.
Second, the interaction between TAMs and PD-1/PD-L1 immune checkpoints - the targets of modern immunotherapy drugs - is a major emerging focus. Understanding how macrophages regulate these checkpoints could explain why some patients respond to immunotherapy and others do not.
Third, detailed investigation of the molecular mechanisms of macrophage polarization (the switching between tumor-fighting M1 and tumor-helping M2 states) is advancing rapidly. Fourth, the chemotherapeutic modulation of TAMs - particularly how irinotecan changes macrophage behavior - is receiving renewed attention as a potential treatment strategy.
The rapid growth of TAMs research in CRC has several potential clinical payoffs. Macrophage-related molecules could serve as diagnostic biomarkers - measurable signals in blood or tissue that indicate disease stage, prognosis, or likely response to treatment.
More directly, TAMs are emerging as therapeutic targets themselves. Current strategies under investigation include blocking the recruitment of macrophage precursors into tumors, forcing M2 macrophages to convert back to M1, enhancing their cancer-cell-eating capacity, and combining these approaches with existing immunotherapy.
The authors highlight that the next frontier will involve multi-omics integration - combining data on genes, proteins, and cellular environments together - along with artificial intelligence tools to predict individual patient responses and design personalized treatment strategies targeting the tumor macrophage ecosystem.
This bibliometric study provides a panoramic view of two decades of research on macrophages in colorectal cancer. The field has grown from basic observations about how macrophages affect chemotherapy to sophisticated investigations of cellular heterogeneity, immune checkpoint biology, and therapeutic targeting.
The concentration of leading research at a small number of Chinese institutions, combined with the United States' broader collaboration network, suggests that international research partnerships will be increasingly important to accelerating translation into patient care.
With publication rates still rising and new technologies like single-cell sequencing and AI-based analysis becoming more accessible, the field of CRC TAMs research is positioned for continued rapid development - and potentially for major clinical breakthroughs in the next few years.