**4. Immune checkpoint inhibitors (ICI) as immunomodulatory agents**

In adaptive immunity, two immune cells, B and T. B-cells, recognize circulating antigens in their natural state and produce protective antibodies in response [41]. T-cells are a powerful weapon the immune system uses to fight cancer [42]. T-cells identify peptide antigens from intracellularly degraded proteins filled onto the Cell's surface of *major histocompatibility complex (*MHC) molecules, and this process is known as antigen presentation [43]. Immunological checkpoints on the cell surface are activated when their surface proteins recognize and bind to partner proteins on other cells, such as specific tumor cells [42]. Self-tolerance requires immune checkpoints to prevent autoimmunity and protect tissues from destruction [44]. Tregs are drawn to cancer cells, which causes them to express less tumor antigen and release immune-suppressive cytokines that activate inhibitory immunological checkpoints [10] that create an immunosuppressive TME [45]. Immune checkpoint inhibitors work by obstructing particular inhibitory pathways' actions to combat immunosuppressive conditions [44]. The "brake system" of the immune system that cancers routinely exploit to halt immunological responses and defend themselves are immune checkpoints. Checkpoint inhibitors can generate new immune responses against cancer and strengthen already-existing ones to remove malignant cells.

The CTLA-4, PD-1, and PD-L1 are the common inhibitory checkpoints [46]. These antibodies have biological effects on different body parts during the T cell's lifecycle [47]. In addition, they functionally complement one another, establishing that T cell responses retain self-tolerance while defending the body from infections and cancer [43]. The immune checkpoint inhibitors approved by the FDA are shown in **Table 1**.

#### **4.1 CTLA-4**

In humans, CTLA4 is the first immune-checkpoint receptor to be studied; its located on T cells and controls T cell activation in the early stages of infection [48]*. CTLA-4* is a novel immunoglobulin superfamily member resembling CD28, structurally and pharmacologically [49]. CTLA-4 and CD28 are expressed exclusively in the hematopoietic compartment and found in the exact location of chromosome 2 (2q33.2). Furthermore, CTLA-4 and CD28 have the most sequence similarity in their extracellular binding domain; they bind to the identical CD80 and CD86 ligands expressed by antigen-presenting cells (APCs) [50]. Further characterization revealed that CD28 and CTLA4 have opposing immunoregulatory functions. CTLA4 inhibits T cell activation in a number of ways, including by directly opposing CD28, competing for co-stimulatory ligands, preventing the production of immunological conjugates,


*CRC, colorectal cancer; HCC, hepatocellular carcinoma; NSCLC, non-small cell lung cancer; RCC, renal cell carcinoma; BCC, basal cell carcinoma; CSCC, cutaneous squamous cell carcinoma; EnC, endometrial carcinoma; EsC, esophageal carcinoma; GC, gastric carcinoma; SCC, squamous cell carcinoma; HL, Hodgkin lymphoma; HNSCC, head, and neck squamous cell carcinoma; UC, urothelial carcinoma BC; Breast cancer; CVC, cervical cancer; MCC, Merkel cell carcinoma; LBCL, large B cell lymphoma; SCLC, small cell lung cancer; dMMR, mismatch repair deficient.*

#### **Table 1.**

*Immune checkpoint inhibitors approved by FDA.*

and recruiting inhibitory effectors [51]. Moreover, CTLA4 promotes the internalization of its ligands, which prevents them from binding to CD28 and reduces IL-2 production and T-cell proliferation [52].
