2.1.2. Innate and Adaptive Immunity in Cancer

Both innate and adaptive immunity are crucial components in cancer development and progression and the overall immune response relies on the interplay between them. Innate immunity involves various types of myeloid cells: dendritic cells (DCs), monocytes, macrophages, polymorphonuclear leukocytes (PMNs), mast cells, NKs, and natural killer T (NKT) cells [26]. The innate immune system can directly inhibit tumor progression by engaging tumoricidal activity with NKs (recognition of tumor-derived antigens), granulocytes, and macrophages through antibody-dependent cellular cytotoxicity (ADCC) or antibody-dependent cellular phagocytosis (ADCP) [28]. Conversely, the innate immune system can also contribute to immunosuppression. A major example is represented by protumorigenic M2-TAMs, which express multiple immunosuppressive (e.g., prostaglandin

E2, IL10) and tumor-promoting factors leading to suppressed anti-tumor responses [29]. In addition to innate immunity, we find cells from the adaptive immune system, i.e., T-cells and B-cells, whose aim is to eradicate cancer or to inhibit their proliferation through cellular and humoral immunity, respectively. This anticancer response relies notably on the cancer immunity cycle (CIC), a process which can be divided into seven stages starting with cancer antigen release (step 1) and finishing with killing cancer cells (step 7: immunogenic cell death, ICD) through CTLs [30]. Thus, CIC can be self-propagating, leading to an accumulation of immune-stimulatory factors that in principle should amplify and broaden T-cell responses. CIC is also characterized by immune regulatory feedback mechanisms capable of stopping or lowering the immune response. Physiologically, immune tolerance regulating immune responses and preventing tissue damage is mediated by immune checkpoints which are negative regulators of T-cell activation. They refer to immunosuppressive molecules which can be highly expressed in cancer, mediating tumor immune evasion. The main immune checkpoints are cytotoxic T lymphocyte antigen 4 (CTLA-4, expressed on the activated CD8+ and CD4+ T cells), programmed cell death protein 1 (PD-1, expressed in myeloid, B- and activated T cells), and programmed cell death ligand 1 (PD-L1, myeloid and cancer cells). These immune checkpoints have given rise to one of the most important immunotherapies based on their inhibition: the ICIs [31]. LAG3, TIGIT, and TIM3 are other checkpoint signaling molecules, among many others, extensively studied to understand their role in T-cell functions and their potential as new immunotherapies for cancer [32]. It is important to point out that innate and adaptive immunity are tightly connected, notably due to the involvement of antigen-presenting cells (APCs: DCs, macrophages) and complement proteins, resulting in the activation of a T-cell response and immunological memory [26]. This underlines the great interest in using therapeutic strategies capable of targeting both innate and adaptive immunity through, for example, "all-in-one" modalities such as nanomedicines [33], radiotherapy [34], hyperthermia [35], or various synergistic combinations [36,37].
