Colorectal cancer (CRC) is a significant global health concern [1], [2]. Incidence among men exhibits 1.2-fold higher than among women [3]. According to GLOBOCAN 2020 databases, CRC is ranked as the third most commonly diagnosed cancer and the second most deadly cancer globally [3]. In Tunisia, according to the North-Tunisia Cancer Registry (NTCR), the prevalence of CRC is estimated at 21.4/100,000 in 2019 and expect to increase to 31.4/100,000 in 2024 [3]. Metastasis is the major cause of death in patients with CRC [4]. The liver is the most common site of distant metastasis, and approximately 15% to 25% of CRC patients have liver metastases at the initial diagnosis [5], [6]. Surgical resection is considered the only potentially curative therapy for colorectal liver metastases (CRLM) and the best opportunity for long-term survival [7], [8], [9]. However, almost two‐thirds of CRLM patients were deemed initially unresectable, and their overall 5-year survival rate ranged from 33% to 50% [10]. The interaction between tumor cells and stromal cells in the tumor microenvironment plays a crucial role in tumor development and is partially mediated by chemokines and receptors [11], [12]. Monocyte chemotactic protein 1 (MCP-1), also called chemokine (C–C motif) ligand 2 (CCL2) [13], [14], is the principal chemokine involved in monocyte and macrophage recruitment [15], [16] and is considered a powerful actor in the promotion of tumor development [17], [18] and immunosuppression [19], [20].

MCP1 is synthesized and secreted constitutively or via stimulations by monocytes, macrophages, fibroblasts, smooth muscle cells, vascular endothelial cells, and tumor cells [13], [14], [21]. MCP-1 modulates the tumor behavior by several important mechanisms: regulation of angiogenesis, activation of a tumor-specific immune response by attracting leukocytes, stimulation of tumor cell proliferation, and invasiveness [14], [22], [23]. Besides, MCP1 promotes monocyte trafficking and recruitment from the bloodstream to the tumor microenvironment (TME), where they give rise to TAM (Tumor-associated macrophage) and induce the phenotypic polarization of macrophage into cancer-promoting M2 phenotype [24], [25], [26]. MCP-1 expression was outstandingly correlated with endothelial–mesenchymal transition in colorectal cancer and is associated with venous invasion, lymph node metastasis, and distant metastasis [16], [17], [18], [27], [28]. High MCP1 serum levels are detected in CRC patients and are correlated with tumor stage and grade [29], [30]. The activation of the MCP1/CCR2 axis induces the activation of several signaling pathways, including G-proteins, the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway, the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, and the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway [23], [31], [32], [33], [34].

MCP-1 is encoded by the CCL2 gene located on chromosome 17 (17q11.2-q12) [13], [14]. Among various polymorphisms, a functional genetic variation within the MCP-1 gene promoter, rs1024611 A > G, was suggested to be associated with cancer susceptibility, including breast cancer, cervical cancer, endometrial carcinoma, cervical cancer, and ovarian cancer, and might be a risk factor for cancer development [23]. MCP-1 expression levels display a significant inter-individual variability attributed to SNPs in the regulatory regions of the CCL2 gene [35].

A previous study reported that an A to G substitution of MCP1 rs1024611 on the transcription start site located in the distal regulatory region influences the transcriptional activity of CCL2 and is associated with increased MCP1 serum level and higher activity under IL1 stimulation, increased cancer risk, and poor prognosis as reported by a recent meta-analysis [36]. MCP-1 exerts its biological activity by preferentially engaging its cognate receptor CCR2, located in chromosome 3(3p21.31) [37]. CCR2 is a pro-inflammatory chemokine receptor mainly expressed by memory T lymphocytes, monocytes, dendritic cells, B-cells, basophils, and tumor cells [38]. The CCR2 rs1799864 polymorphism has been described to be associated with cancer susceptibility such as bladder and cervix cancer [39], [40], induced valine change to isoleucine at codon 64 (CCR2V64I), reported to affect CCR2A isoform by increasing its expression, extending its half-life, and enhancing stability which requires a higher concentration of its ligand MCP1 [39], [40], [41], [42], [43], [44], [45].

Given the critical role of MCP1 and CCR2 gene variants in tumor progression, we conducted this case-control study to examine the possible implication of these two polymorphisms, MCP1 rs1024611 and CCR2 rs1799864, with CRC and CRLM in the Tunisian population.