## 1 Introduction  
Cancer is one of the most common diseases and the leading cause of death worldwide in the last decades. Furthermore, in the last two decades, there have been approximately 20 million new cancer cases per year, according to World Health Organization in 2024, accounting for nearly 10 million deaths [1; 2], making it the second deadliest disease in the United States, after heart disease [1; 2; 3]. Breast cancer seems to be the most common type of cancer among females, while lung cancer is not only the commonest one in the male population but also the deadliest one, regardless of gender [2]. After years of research, a promising treatment option of immune checkpoint inhibitors emerged, such as anti-CTLA-4 and anti-PD-1/PD-L1, but only a small amount of data are known about their effect on B cells. Undeniably, the immune system's role in cancer pathophysiology has been the center of investigations during the last decades. Cancer acceleration and proliferation depend on the equilibrium among cancer immunosurveillance, genetic instability, immune homeostasis, and the ability of cancer cells to escape detection [4]. Cancer cell evasion can occur through activating negative regulatory pathways (checkpoints), such as cytotoxic T-lymphocyte protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) [5; 6]. CTLA-4 is a protein receptor that is expressed on the surface of T cells and, by competing for the co-stimulatory molecule CD28 for binding to CD80 and CD86 ligands, downregulates the naive T cell activation in the initial stages. Alongside this, antigen-stimulated T cells express PD-1 receptors on their surface, that bind to its ligand PD-L1 or PD-L2, and inhibit T cell proliferation, cytokine release, and cytotoxicity [5; 7]. PD-1 is a type I transmembrane glycoprotein of 288 amino acids that is encoded by the PDCP1 gene in chromosome 2 and belongs to the CD28 family. It is expressed on the surface of T cells, B cells, dendritic cells (DCs), activated monocytes, natural killer cells (NKs), macrophages, and many tumor-infiltrating T cells (TILS). It has two ligands that belong to the B7 family: PD-L1, a type I transmembrane protein of 290 amino acids encoded by the CD274 gene in chromosome 9, and PD-L2, a protein of 273 amino acids encoded by the CD273 gene. PD-L1 is expressed in resting T cells, B cells, DCs, macrophages, monocytes, vascular endothelial cells, pancreatic islets, and many types of cancer cells, whereas PD-L2 is expressed in macrophages, DCs, and mast cells. Multiple proinflammatory molecules that are produced by tumor microenvironments (TMEs), such as INF-\(\gamma\), TNF-\(\alpha\), IL-2, IL-10, GM-CSF, VEGF, and oncogenes such as PTEN, induce the upregulation of PD-L1 [8; 9; 10; 11; 12; 13; 14]. Under normal circumstances, the PD-1/PD-L1 signaling pathway plays a critical role in the homeostasis of the immune system in response to inflammation (infection, cancer etc. ), avoiding overstimulation of effector T cells, hence protecting the healthy tissues and avoiding autoimmunity [15; 16]. However, many cancer cells overexpress the PD-L1, helping the tumor cells to evade the immune surveillance by inducing apoptosis of activated effector T cells, driving them into exhaustion, inhibiting their proliferation, and enhancing the function of regulatory T cells (Tregs) [8; 9; 17; 18]. Through these interactions, the tumor disrupts the equilibrium between suppressive and promoter anticancer factors, inducing its acceleration and metastasis. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies (mAbs) that block the PD-1/PD-L1 and CTLA-4 axis, promoting a dynamic and limitless anticancer response of effector T cells.