Chapter 1 │ Page 13 di erent cancer types: PD-1 inhibitors (e.g., Pembrolizumab), PD-L1 inhibitors (e.g., Durvalumab), and the CTLA-4 inhibitor Ipilimumab [22-25]. Immune checkpoints, like the PD-1/PD-L1 axis and CTLA-4, serve as key negative regulators of T cell function, maintaining the delicate balance between pro- and anti-inflammatory signals under homeostatic conditions [26, 27]. However, tumors exploit and overexpress these pathways to evade immune surveillance, e ectively damping the immune system [27]. By blocking these inhibitory signals with monoclonal ICI antibodies, immune tolerance can be prevented or reversed, thereby also allowing for intervention at multiple steps of the cancer-immunity cycle [12]. Herein, ICIs reinvigorate the host immune system to recognize and eliminate tumor cells by enhancing T cell activity at several critical points (Figure 1), including T cell priming and activation in the lymph nodes and during T cellmediated tumor destruction [12, 28]. As T lymphocytes attack and kill tumor cells, this leads to increased tumor cell death and release of additional tumor-associated antigens, so also fueling the principal steps in the front end of the cycle. Despite this success, ICI and other immunotherapies are not universally e ective or suitable for all patients. A major challenge is the overall limited response rate, although highly dependent on the tumor type, with only 15 to 30% of patients initially benefiting from ICI treatment [29, 30]. Additionally, some patients develop acquired resistance, a poorly characterized and highly variable phenomenon across di erent cancer types [31]. Another aspect are the immune-related adverse events (irAEs), a common consequence of ICI, occurring in approximately 90% of patients treated with anti-CTLA-4 and 70% of those receiving anti-PD-1/PD-L1 inhibitors, although in various grades[32]. Furthermore, the combination of both ICI is reported to increase the observed irAEs [32, 33]. As a result, the full potential of immunotherapy remains constrained, highlighting the urgent need to improve its e icacy while reducing toxicity.
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