Gastrointestinal cancers account for over a quarter of all cancer incidence globally and contribute to approximately one-third of cancer-related fatalities(Huang et al., 2023; Xia et al., 2022). Despite significant advancements in colorectal cancer (CRC) screening, the prognosis for most gastrointestinal cancers remains unfavorable (Arnold et al., 2020, Poisson et al., 2021; Yang, J. et al., 2021). In East Asia, the incidence of gastrointestinal tumors, such as CRC, has been steadily rising, with an emerging trend of increased incidence among younger individuals(Cao et al., 2021; Huang et al., 2023). Traditional chemotherapy, radiotherapy, and the latest immunotherapies pose significant clinical challenges in the treatment of gastrointestinal tumors. For instance, a clinical study on esophageal adenocarcinoma revealed that only 29.3% of patients achieved a pathologic complete response (PCR) to neoadjuvant chemoradiotherapy (Leng et al., 2020, Rizzetto et al., 2008). No statistically significant differences were observed in overall survival and disease-free survival between patients achieving neoadjuvant therapy complete pathologic response (Alves et al., 2022). Furthermore, pancreatic cancer inherently exhibits resistance to treatment, with a less than 5% five-year survival rate (Collisson et al., 2019, Klein, 2021, Neoptolemos et al., 2018). Consequently, there is an urgent need for novel targeted therapeutic agents to enhance the treatment sensitivity of gastrointestinal cancers.

In recent years, research has highlighted the crucial role of the TME in the development and treatment resistance of gastrointestinal cancers(Zheng et al., 2022). Although the composition of different tumor microenvironments varies significantly, infiltration of myeloid cells, particularly monocytes, macrophages, and dendritic cells, is a common characteristic in gastrointestinal tumors (Ai et al., 2023, Long et al., 2017). Recent studies suggest that myeloid cells within the tumor immune microenvironment may play a significant role in the development of chemotherapy resistance and immune evasion in gastrointestinal cancers (Barry et al., 2023). Some studies have found that myeloid lineage cells can reduce the efficacy of radiotherapy and chemotherapy through various mechanisms, such as inhibiting tumor oxidative stress response, influencing DNA damage response, or promoting tumor cell repair mechanisms(Gao et al., 2022; Kim et al., 2019). Furthermore, certain myeloid cells, such as MDSCs, are recruited and exhibit immune-suppressive characteristics in gastrointestinal tumors. They can inhibit immune responses, thereby hindering an effective immune response against the tumor(Leinwand and Miller, 2020; Väyrynen, S.A. et al., 2021). Traditional radiotherapy and chemotherapy lack the specificity to target tumor cells selectively(Gamboa et al., 2020; Jackson et al., 2019). Therefore, although intensifying chemotherapy may enhance its anti-tumor effects, it also increases toxicity to normal tissues(Byrd et al., 2021; Fehlings et al., 2016). Additionally, the complexity and heterogeneity of the TME mean that targeting specific features within the tumor immune microenvironment, such as the expression of immune checkpoint receptors (e.g., PDL1 and PDL2), alone may not effectively overcome chemotherapy resistance and immune escape mechanisms(Burr et al., 2017; Kornepati et al., 2022; Shen and Zhao, 2018). Therefore, combination targeted therapy strategies, especially combining immune-targeted therapies with traditional chemotherapy and precision medicine, may offer an effective approach to address these challenges. Within the tumor microenvironment, myeloid cells have a crucial role in forming a tumor immune-suppressive microenvironment. They also enhance tumor resistance to chemotherapy through mechanisms such as the expression of inhibitory receptors and the release of pro-angiogenic factors. (Ohnuki et al., 2014, Väyrynen et al., 2021, Zheng et al., 2021). Consequently, targeting myeloid cells and implementing combination therapy strategies are considered a pivotal approach to overcome chemotherapy resistance and immune escape mechanisms in current cancer treatment.

Therefore, this paper delves into the key characteristics of myeloid cells within the tumor microenvironment, such as their interaction with tumor cells, including promoting the expression of drug-resistant proteins and immune evasion. They also secrete immune-suppressive factors, induce immune cells to polarize towards an immune-suppressive phenotype, thus exerting immune inhibitory effects to prevent the destruction and clearance of tumor cells by immune cells like T cells and NK cells. Furthermore, they induce pro-tumoral inflammation, facilitate the invasion and metastasis of tumor cells into surrounding tissues, and promote angiogenesis. Furthermore, we conducted an analysis based on in vitro and in vivo studies, as well as clinical data from patients, to assess the potential clinical applications of targeting myeloid cells to enhance the response of gastrointestinal cancers to conventional chemoradiotherapy and immunotherapy, as well as to address issues related to chemotherapy resistance and immune escape in cancer treatment. Additionally, we provide an overview of strategies employing myeloid cells, especially TAMs, as tools and targets in the treatment of gastrointestinal tumors. These strategies encompass the roles of TAMs in conventional cancer therapy and checkpoint blockade, strategies for reshaping and activating TAMs, metabolic immune approaches, and engineered macrophage-based therapies.