1. Introduction

A malignant growth that originates near the end of the intestine is known as colorectal cancer (CRC). Usually, it commences as an abnormal intestinal lining expansion and grows over time to evolve into a tumor. Radiotherapy, chemotherapy, and operations compose nearly all of hospital treatment. Tumor immunotherapy and targeted therapy have been developed frequently in recent years to treat carcinoma of the colon. The approach to the therapy of malignancies evolved tremendously as an effect of immunotherapy

The tumor microenvironment, also known as the TME, initially has unique pro-tumor and anti-tumor effects in the early stages of the growth of the tumor. Nevertheless, as distinct cells called stromal cells in the TME interact with tumor cells, a TME which fosters tumor development subsequently forms. The CRC microenvironment has a variety of immune cells that are necessary for anti-tumor immunity.The investigation on immunosuppressive cells and colorectal cancer has been reviewed in this article, it additionally presents more theoretical guidance on colorectal cancer treatment in the future.

2. Application of major immunosuppressive cells in colorectal cancer

2.1. Tumor-associated macrophages (TAMs)

2.1.1. Source and mechanism of action of TAMs

Metastatic-associated macrophages, or TAMs, are the most prevalent immune system the subgroup in the tumor microenvironment inside of the tumor ambiance. TAMs are generated by a range of sources, though the two biggest ones are circulating monocytes that are drawn to the tumor site by tumor tissues and cells and disease penetrating macrophages at the exact location of the tumor. These cells have a capability to self-renew while also to becoming tissue-specific. Tumor development angiogenesis, metastasis, control of metabolism, immunosuppression, treatment resistance, and microbial ecological oversight are among the biological processes in which they are vital. Likewise they establish an extensive connection with elements of the tumor microenvironment, which includes extracellular matrix (ECM), cytokines, fibroblasts related to cancer (CAFs), and other immune cells. If various microenvironmental cues happen, TAMs can polarize into the M1 type tumor suppressor and the M2 type tumor promoter; M2 TAMs predominance in tumors that are proliferating. The important role of TAMs in tumor immune escape, growth and development, and metastasis, as well as their potential as therapeutic targets, has continually come into focus for the scientific community as TME research keeps progressing.

2.1.2. Role of TAMs in colorectal cancer

Through their participation in coupled signaling pathways and gene regulatory networks, TAMs regulate the growth of tumors and play an essential role in the development of cancer of the colon. In tandem, small extracellular vesicles (sEV)-miR-21-5p and sEV-miR-200a from CRC may lead TAMs to polarize toward the tumor-promoting M2 type. That may further enhance TAMs-mediated CD8+ T lymphocyte suppression, immune escape, and CRC progression by impacting the phosphatase tensin homolog/protein kinase B (Akt) and inhibitor of cytokine signaling 1/STAT1 signaling pathways [1].

2.1.3. TAMs in the treatment of colorectal cancer

Targeting TAMs is predicted to become an effectively anti-tumor approach due to the crucial role that TAMs plays in tumor expansion and metastasis. The primary objectives of this approach to therapy are inducing phenotypic conversion of TAMs or weakening their tumor-promoting function in order to achieve functional transformation and minimizing the number of TAMs by either entirely eliminating TAMs who are already present in the tumor microenvironment or averting their recruitment to the tumor. The two methods may effectively decrease the push of TAMs forming cancers.Numerous immunotherapy approaches that target TAMs have recently been investigated. By restricting the CCL5-CCR5 signaling pathological and avoiding TAM migration into tumor tissues, the CCL5-CCR5 inhibitor the maraviroc may substantially halt the spread of colorectal cancer by blocking TAM polarization to M2 [2].By blocking the growth of M2 TAMs and myeloid-derived suppressor cells brought on by PGE2 receptor 4, TP-16, an inhibitor of the prostaglandin E2 (PGE2) signaling pathway, may dramatically boost the activity of immune cells that permeate tumors [3].

2.2. Regulatory T cells (Treg)

2.2.1. Source and mechanism of action of Treg cells

Treg cells were first identified in the 1990s as CD4+ T cells that showed elevated CD25 expression in mice that could safeguard autoimmune tolerance. By restricting the immune response mediated by immune cells consisting of effector T cells, cells of the mast, dendritic cells, as well as B cells in addition to inhibiting the biological functions associated with specific non-immune cells in the tissue microenvironment, treg cells precisely influence the body's response level to foreign or self-antigens in order to maintain the body's immune tolerance. The characteristic protein of Treg cells, forked head transcription factor 3 (Foxp3) refers to the forked head transcription factor family.As a transcriptome regulator or simply a Foxp3 serves as crucial for controlling the body's autoimmunity and can control Treg activity. Severe autoimmune and other infections can be called on by mutations in the Foxp3 gene. As a result, Foxp3 is critical to sustaining immunologic homeostasis in the body. Some malignant tumors have been found to have Treg infiltration. Foxp3+Treg suppresses anti-tumor immunity, which stimulates proliferation of tumors and spread.A number of research efforts found that Treg cells multiply in the carcinoma tissues close to many kinds of malignancy, including melanomas, breast, colorectal, lung, and tumors of the pancreas. Multiple research efforts indicate that an increase in the tumor microenvironment's Treg cells is connected to a poor prognosis and that it could lead to in-tumor immune escape.From a technical point of view, the production of Treg can be determined by a number of substances in the TME, which is unique to the normal Treg the growth process. Among them, chemokines have a knack to bring Treg to the tumor from peripheral blood, lymph nodes, the marrow of the bones, and the thymus contribute to Treg development.Treg maturation and proliferation can also be promoted by faulty antigen-presenting cells.

2.2.2. Role of Treg cells in colorectal cancer compared

Treg cell infiltration is higher in the tissues of CRC than in normal and surrounding tissues, and it is more substantial in the regional lymph nodes close to the tumor than in distant and non-regional lymph nodes. By expressing CD39 and enhancing the formation Comprising programmed death receptor-1 (PD-1) and cytotoxic T lymphocyte antigen-4 (CTLA-4),tregs boost their immunosuppressive physical activity [4].Through the secretion of IL-10 and IL-35, they can also jointly influence CD4+ and CD8+ TILs' BLIMP1 inhibitory receptor axis, hampering the success of antitumor immunity [5].Additionally, Tregs may inhibit the rapid growth of colorectal cancer cells by decreasing the synthesis of IL-6 and suppress Th1 secretion of angiogenesis inhibitory factors by limiting Th1 biological activity. They also have separate responses to tumor-specific antigens.

2.2.3. Treg cell therapy in colorectal cancer

Preclinical as well as clinical investigations have previously shown that shrinking Treg cells amplifies the beneficial effects of cancer therapy. Treatment strategies that utilize the Treg surface receptor polypeptide A repeat sequence have also been researched. The surface of activated Treg cells generates glycoprotein A repeat sequences (GA-RP, Glycoprotein A repeats predominate), which may bind to and activate TGF-β and are related to immune escape and disease progression. Research suggests GARP-deficient Tregs had a lower ability to inhibit inflammatory responses, boosted immunity against tumors along with slower tumor growth in a model of colon cancer associated with colitis [6].In animal models of carcinoma of the colon, this approach significantly boosted the curative power of drugs that inhibit PD-1[7].The technique was looked into in phase I for metastatic non-small cell lung cancer (NCT 03181308), and more research must be done to assess whether it may serve as a target for cancer of the colon.

Peripheral Treg cells and Treg cells in tumor-infiltrating platforms both decline as a result of Treg cell weariness. This might lead to the emergence of autoimmune illnesses by impairing the way the immune system responds to self-antigens. For it to avoid autoimmune ailments, the best Treg cell-targeted immunotherapy should preserve peripheral Treg cells while deleting Treg cells from the TME.

2.3. Myeloid-derived suppressor cells (MDSCs)

2.3.1. Source and mechanism of action of MDSCs

Immature granulocytes, macrophages, and dendritic cells are among the diverse cells referred to as MDSCs, which share an immunosuppressive role and a myeloid origin and are seen in individuals as well as animals with tumors. The knack of MDSCs to aid in tumor immune escape has been an area of thorough research in recent years, making it a key target for anti-tumor immunotherapy. Tumors, inflammation, and infection with pathogens are examples of abnormal situations when myeloid cells multiply abnormally to congregate and create MDSCs.

2.3.2. Role of MDSCs in colorectal cancer

The value of MDSCs to regulating the growth of colorectal cancer has grown in recent years, and it is now a popular area of exploration. Currently, CD11b+HLA-DR-Lin-CD33- and its functional markers are the least well-known MDSC phenotype. Due to research the results, MDSCs in peripheral blood and tumor tissues are risk factors for the development of colorectal cancer and have a strong connection with the stage of the disease and the development of tumors in both mice models and humans with the illness [8]. Experimental results demonstrated that MDSCs were concentrated in the peritoneal cavity upon tumor evacuation in mice with colorectal cancer and were linked to a poor prognosis. In line with the findings, MDSCs convey a significant challenge to cancer immunotherapy [9]. Thus, the development of neoadjuvant treatment targeting MDSCs must be taken into attention in order to increase the overall survival rate of patients with colorectal cancer and reduce the possibility of tumor distribution.

2.3.3. Treatment of MDSCs in colorectal cancer

Nowadays, doxorubicin, 5-fluorouracil, and gecitabine are common pharmaceuticals used in tumor chemotherapy. They cause cell apoptosis, which lowers the quantity of MDSCs. Those drugs may have synergistic effects when employed in combination with immune checkpoint medications. Investigation has demonstrated that the combination of bevacizumab with FOLFOX (5-fluorouracil+oxaliplatin) chemotherapy can more successfully decrease the level of PMN-MDSCs and their immunosuppressive activity in patients with metastatic colorectal cancer, enhancing the prognosis for those with the disease [10]. PD-1 and CTLA-4 the immune system checkpoint inhibitor therapy works well for dMMR/MSI-H tumors, whereas the immune response is weak for pMMR/MSI-L tumors. Immune-suppress cells (MDSCs and regulatory T cells) are more frequently found in pMMR/MSI-L tumors than in dMMR/MSI-H tumors [11]. As an outcome, people suffering from pMMR-MSI-L colorectal cancer might gain from adopting MDSCs-targeted rehabilitation to assist strengthen outcomes after surgery.

3. Conclusion

Immunosuppressive cells have an assortment of beginnings, sophisticated mechanisms of action, and numerous applications in the emergence and dissemination of cancers. Multiple immunosuppressive cell types collaborate with other kinds of cells in the tumor microenvironment, controlling growth of tumors and metastasis altogether. These are crucial to the entire CRC microenvironment and may make an important influence on the way that anti-colorectal cancer treatment regimens act.Consequently, it seems likely that specific therapy for different kinds of immunosuppressive cells will become available as an innovative way for battling colorectal cancer. A number of medications are now in the clinical trial stage, and these kinds of treatments are sure to contribute to improving the effectiveness of CRC immunotherapy in the near future. Discovering an exceptionally effective method is still exceedingly challenging because of the complexity of connections between immunosuppressive cells and other cells and substances, as well as its inherent heterogeneity. Future preliminary investigations are needed to reveal complex heterogeneity, collaborating networks, and control of phenotypic adaptations of various varieties of immunosuppressive cells.

Establishing a bridge between the requirements of clinical practice and academic pharmaceutical research is the essence of unique drug research and development. We must first overcome the bottleneck of new drugs being developed, count on the scientific research motor, and closely integrate with clinical practice to provide innovative medicines for the future by frequently boosting the mutual feedback and synthesis of pharmaceutical theory and clinical practice.