*3.2. Immune Cycle in Cancer*

For the immune response against cancer to be effective in destroying/eliminating cancer cells, certain events must occur in a staggered and continuous manner. These events are also steps in the "cancer immune cycle" (Figure 5).

The release of neo-antigens (formed from the oncogenesis) is subsequently captured by the dendritic cells (DC) to be processed (Step 1). For this to produce an anticancer T-cell response, it must be accompanied by signals that specify immunity, thus avoiding the induction of peripheral tolerance to tumour antigens. These signals can be pro-inflammatory cytokines and factors released by damaged tumour cells. DCs then present the neoantigens on MHC-I and MHC-II molecules to T cells (step 2). Antigenic presentation on MHC molecules activates effector T cells against specific cancer antigens (step 3). It is in this step that the nature of the immune response is determined, establishing a balance between effector T cells and regulatory T cells. The effector T cells then migrate to the tumour site (step 4), infiltrating the tumour bed (step 5). Once here, the T cells specifically recognize the cancer cells and bind to them through the interaction between the T Cell Receptor (TCR) and its related antigen bound to MHC-I (step 6). Finally, the T cells kill the target cancer cell (step 7). Killing the cancer cell will release tumour-associated antigens (TAAs), causing the cycle to restart. This increases the breadth and depth of subsequent responses [76].

**Figure 5.** Schematic description of cancer immune cycle.

In cancer patients, this cycle does not work properly, with errors in the different steps described above: tumour antigens are not detected, DCs and T cells do not treat the antigens as foreign, the response is greater in regulatory T cells than in effector cells, T cells do not infiltrate tumours adequately, or even multiple factors in the tumour microenvironment may inhibit effector T cells. Bearing this in mind, the goal of cancer immunotherapy is to initiate a self-reliant cycle of cancer immunity that can amplify and spread without generating an unchecked auto-immune inflammatory response. To achieve this, immunotherapy must escape negative feedback mechanisms (checkpoints and inhibitors). Although amplifying the entire cell cycle provides anti-cancer activity, it generates damage to normal cells and tissues in return which might be drawback or source for resistance to the treatment. Recently, several clinical studies suggest that a common rate-limiting step is "immunostat function", which is the immunosuppression that occurs in the tumour microenvironment [76].

As discussed above, different immunotherapies can act on the several phases of the cancer immune cycle to ensure that an effective immune response is generated against the tumour cells.
