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Review
. 2025 Aug 12:16:1642091.
doi: 10.3389/fimmu.2025.1642091. eCollection 2025.

Tumor-associated macrophages in colon cancer immunotherapy: mechanisms, natural product interventions, and microenvironment remodeling

Qingman He  1 , Li Xiang  1 , Yuanyuan Luo  1 , Rongrong Wang  2 , Chuan Zheng  3   4 , Yongxiang Gao  1 , Huan Yao  3   5
Affiliations
Review

Tumor-associated macrophages in colon cancer immunotherapy: mechanisms, natural product interventions, and microenvironment remodeling

Qingman He et al. Front Immunol. .

Abstract

Colon cancer persists as a major global health burden due to therapy resistance and metastasis, with tumor-associated macrophages (TAMs) in the microenvironment driving progression through immune evasion and angiogenesis. This review highlights plant-derived therapeutics targeting TAMs to disrupt protumor signaling. Key phytochemicals (e.g., Curcumin, Cucurbitacin B, Astragaloside IV) suppress M2 polarization via NF-κB/STAT3 inhibition, block VEGF/HIF-1α-mediated angiogenesis, and enhance antitumor immunity by downregulating PD-L1. Cannabidiol, Hydroxygenkwanin regulate TAM metabolism. Dietary agents like sulforaphane and β-glucans modulate TAM-gut microbiome crosstalk. Nanoparticle-encapsulated phytochemicals enhance TAM-targeted delivery, while clinical translation requires standardized phytopreparations and biomarker-guided trials. We propose integrating validated botanical adjuvants (e.g., Fucoidan for TLR4 inhibition, dihydroisotanshinone I for CCL2 suppression) with immunotherapies to remodel immunosuppressive niches. Phytotherapy offers a multifaceted strategy to overcome TAM-driven therapeutic barriers in colon cancer, emphasizing plant-based precision medicine to augment conventional treatments.

Keywords: colon cancer; immune checkpoint; nanoparticle delivery; phytochemicals; tumor-associated macrophages.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Multifaceted roles of TAMs in colon cancer progression and microenvironment regulation (Created in BioRender. qingman, H. (2025) https://BioRender.com/t5uzu98). (A) Peripheral monocytes are recruited by chemokines and differentiate into TAMs. Depending on external stimuli, TAMs polarize into the M1 phenotype, which releases pro-inflammatory factors with anti-tumor and immune-activating functions, or the M2 phenotype, which secretes anti-inflammatory mediators that promote tumor growth and angiogenesis. (B) In colon cancer, TAMs predominantly exhibit the M2 phenotype. The TAMs contribute to shaping the inflammatory milieu, promoting EMT, remodeling the ECM, and secreting cytokines, chemokines, and proteases that enhance tumor cell proliferation, invasion, and migration. (C) TAM-mediated angiogenesis and metastasis in colon cancer. (D) TAMs shape an immunosuppressive microenvironment by secreting inhibitory factors, recruiting Tregs and MDSCs, and suppressing the functions of cytotoxic T cells and dendritic cells. Meanwhile, colon cancer cells evade macrophage-mediated clearance through phagocytosis checkpoints such as CD47-SIRPα, CD24-Siglec-10, MHC-I-LILRB1, and PD1-PD-L1. (E) Gut microbiota modulates TAM phenotypes, exerting dual roles in both promoting and suppressing colon cancer progression.
Figure 2
Figure 2
Intercellular communication via exosomes in colon cancer TME (Created in BioRender. qingman, H. (2025) https://BioRender.com/ijd8zht). (A) Tumor cell-derived exosomes regulate TAMs polarization. (B) TAMs-derived exosomes promote tumor progression.
Figure 3
Figure 3
Natural product–mediated signaling pathways in TAMs polarization (Created in BioRender. qingman, H. (2025) https://BioRender.com/3g8lx62).
Figure 4
Figure 4
Potential strategies for targeting TAMs in the treatment of colon cancer.
See this image and copyright information in PMC

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