Cancer is a devastating disease and remains a significant public health issue globally [1]. Although cancer is fundamentally a disease of the genes, it creates a complex and intricate interaction between the uncontrolled proliferation of tumor cells and the host response. With the immune system's involvement increasingly understood, various anti-tumor immune therapies are being investigated, with many intriguing new avenues to pursue. Given this shift, the complement system is just beginning to emerge as a novel target for anti-cancer therapy. The complement system appears to be a “double-edged sword” [2]. While the complement system is a key component of innate immunity and can support the clearance of altered or stressed cells including tumor cells, its precise role in directly recognizing and eliminating tumor cells remains unclear, and under certain conditions, complement proteins may actually facilitate tumor growth [3], [4]. This dual role illustrates the complex link between cancer and the immune system and emphasizes the necessity to understand complement's role in cancer biology.

The complement system fights microbes, clears immune complexes, and mediates inflammatory responses as part of innate immunity [5], [6]. It is composed of more than 32 different proteins, including cell membrane receptors, serum proteins, and serosal proteins. The complement system can be activated by three different pathways: the classical pathway (CP), the alternative pathway (AP), and the lectin pathway (LP) [7], [8]. The AP is initiated by spontaneous C3 hydrolysis, while the CP and LP are initiated by antibody- and carbohydrate-mediated recognition. These three processes produce C3 convertases (CP/LP: C4bC2b; AP: C3bBb) that split C3 into C3a and C3b. C3b opsonization of pathogens and host cell debris enables their phagocytosis. C3b binding to C3 convertases converts them into C5 convertases (CP/LP: C4bC2bC3b; AP: C3bBbC3b). The C5 convertases cleave C5 into C5b and C5a. C5b triggers assembly of a membrane-attack complex (MAC, C5b-9) which can induce osmotic lysis of the target cell by pore formation or by regulated cell killing in a process similar to apoptosis [9], [10]. Through binding the G protein coupled receptors C3aR and C5aR, the anaphylatoxins C3a and C5a are potent chemoattractants for monocytes, neutrophils, eosinophils, macrophages, and mast cells [7], [11]. In addition, the opsonins C3b and C4b on target cells are engaged by phagocyte receptors including complement receptor 1 (CR1) to aid phagocytosis [12]. The complement system is an effective immune surveillance system and helps maintain homeostasis [13], [14]. When a malignancy develops, this homeostasis is perturbed, and the immunosuppressive functions of complement components can supersede the immune stimulatory effects [4], [15], [16]. Cancer cells use several protective mechanisms to inhibit complement activation, reducing membrane-inserted C5b-9 complexes on the cell surface and creation of anaphylatoxins. Simultaneously, cancer cells initiate many defensive pathways to resist MAC-induced apoptosis [17]. The membrane regulatory proteins, CD46, CD55, and CD59, and the soluble regulator complement factor H (CFH), block complement activation or complement dependent cytotoxicity (CDC) [2], [18], [19]. In addition, complement regulatory proteins (CRPs) can serve as biomarkers for malignant transformation in numerous cancer types and inhibit anti-tumor therapy [19].

This review examines the complex relationship between CRPs, tumor growth, and host immune response. We examine the use of monoclonal antibodies (mAbs) and small chemical inhibitors to target these regulators and report on results of preclinical and clinical research on CRP-targeted treatments. We will also discuss tumor heterogeneity, potential off-target effects, and the emergence of resistance mechanisms, providing a comprehensive overview of the challenges and opportunities in complement field as it relates to cancer