Journal Article

Association of intratumoral CD68+CD163+ M2-like macrophages with survival in metastatic colorectal cancer treated with chemotherapy plus bevacizumab

Qiu, Huixian, Xin, Xiaobin, Qin, Tao, Zhou, Lei, Kong, Qingnuan, Zang, Yan

2026

Overview

BackgroundMetastatic colorectal cancer (mCRC) is a common and highly lethal gastrointestinal malignancy. Although chemotherapy combined with bevacizumab is a standard first-line treatment, post-treatment resistance severely limits patients’ long-term survival. While the remodeling of tumor-associated macrophages (TAMs) is closely related to targeted therapy resistance, the specific impact of TAMs and their programmed death-ligand 1 (PD-L1) expression on post-treatment resistance and prognosis remains unclear. This study aimed to investigate the spatial distribution and immunophenotypic characteristics of CD68+CD163+ M2-like TAMs and their association with post-treatment resistance and survival.MethodsWe retrospectively analyzed clinical data and tumor tissues from 44 patients with mCRC who received first-line chemotherapy plus bevacizumab and were categorized into resistant and non-resistant groups. Multiplex immunofluorescence and digital image-based quantitative analysis were used to evaluate macrophage markers (CD68 and CD163) and PD-L1 expression in the whole tumor section, tumor areas, and stromal areas.ResultsCompared with the non-resistant group, resistant patients showed significantly increased proportions and densities of CD68+CD163+ M2-like TAMs and CD68+CD163+PD-L1+ M2-like TAMs in the tumor areas (all p < 0.05). The infiltration levels of these macrophage subsets were significantly associated with post-treatment resistance, but not with conventional clinicopathological features such as sex, age, or tumor stage. Survival analysis showed that a high density of intratumoral CD68+CD163+ M2-like TAMs was significantly associated with shorter overall survival (OS) (p < 0.05) and showed a trend toward shorter progression-free survival (PFS) (p = 0.06). Multivariate Cox regression further demonstrated that dense intratumoral infiltration of CD68+CD163+ M2-like TAMs was independently associated with unfavorable OS and PFS.ConclusionIn mCRC patients exhibiting resistance to chemotherapy combined with bevacizumab, the infiltration of intratumoral CD68+CD163+ M2-like TAMs and their PD-L1-expressing subsets is significantly elevated. Notably, a high density of intratumoral CD68+CD163+ M2-like TAMs serves as an independent poor prognostic marker for both PFS and OS. These findings demonstrate that the spatial enrichment of CD68+CD163+ M2-like TAMs within the tumor microenvironment is closely associated with treatment resistance, suggesting that macrophage-targeted interventions may represent a potential strategy to enhance the efficacy of anti-tumor therapies in mCRC.

• Publisher: Frontiers Media S.A
• Subject: bevacizumab resistance / M2-like macrophages / metastatic colorectal cancer / multiplex immunofluorescence / PD-L1 / prognosis