Colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related mortality worldwide. Currently, surgical resection remains the cornerstone of curative treatment for CRC; however, patients with advanced disease continue to face significant risks of postoperative recurrence and metastasis. Although immune checkpoint inhibitors (ICIs), represented by PD-1/PD-L1 monoclonal antibodies, have reshaped the therapeutic landscape of various solid tumors, their clinical benefit in CRC is strictly limited by mismatch repair (MMR) status, leaving the vast majority of proficient mismatch repair/microsatellite stable (pMMR/MSS) patients with minimal therapeutic gain. Importantly, tumor-associated macrophages (TAMs)-a key regulatory component of the tumor immune microenvironment-not only exert immunosuppressive functions through PD-1 and multiple other pathways, but also promote PD-1 expression on tumor cells via distinct mechanisms. Consequently, accumulating evidence suggests that TAMs play a critical role in mediating resistance to PD-1/PD-L1 inhibitors in CRC. Nevertheless, research on the underlying mechanisms remains at an early stage. This narrative review aims to summarize the latest advances regarding the involvement of TAMs in resistance to PD-1/PD-L1 blockade, with a particular focus on strategies to enhance immunotherapy responsiveness through TAM modulation. We further discuss limitations in current clinical studies and propose potential directions for future research. By juxtaposing successful mechanistic studies with underwhelming clinical trial data, we aim to redefine the therapeutic rationale for combining TAM-targeted agents with immune checkpoint blockade.
Ning et al. (2026) studied this question.