Chapter 3 │ Page 69 13]. These hurdles underline the need for strategic treatment additions that enhance tumor immunogenicity and reduce systemic toxicity. While traditional therapies primarily focused on direct tumor killing, thereby often inducing non-immunogenic forms of cell death, the consensus is now that more immune-centered approaches hold the greatest potential[14-16]. It could be appreciated that triggering an immunogenic response, beyond solely tumor cell elimination, can enhance long-term anti-tumor immunity and treatment e icacy. Immunogenic cell death (ICD) is a specialized type of regulated cell death, that is characterized by the presentation and release of several damage-associated molecular patterns (DAMPs) that can trigger the immune system[17]. The three main hallmarks of ICD are defined as: i) the exposure of calreticulin (ecto-CRT) on the surface of the cancer cell in the pre-apoptotic phase, ii) the active secretion of ATP, and iii) the release of high-mobility group box 1 (HMGB1) post-mortem [17-20]. Besides this specific spatiotemporal process, additional DAMPs contribute significantly to this immunogenic cell death modality, including the presentation of heat-shock proteins (HSP70/90) and the release of Annexin A1, type I interferons (IFN), and various cytokines (e.g. IL-1β) and chemokines (e.g. CXCL10) [18, 20-23]. These adjuvant signals can trigger adaptive immunity responses via initiation and reinforcement of the cancer-immunity cycle, a series of immunologically critical events required for an adequate anti-tumor response. Profound ICD induction can support multiple of these steps ; for instance, CRT acts as an “eat-me” signal, while ATP functions as a “find-me” signal, both facilitating tumor antigen release and antigen presentation by antigen-presenting cells, corresponding to step 1 and 2 of the cycle, respectively [15, 18, 19, 24]. This boost of the front-end of the cancer-immunity cycle can subsequently lead to more e icient antigen processing, T-cell priming, and following steps in the back-end of the process. Hence, ICD-inducing therapies provide the dual benefit of direct tumor cell elimination and systemic immune
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