Chapter 1 │ Page 14 1.3. Strategies to Tackle Current Limitations of Immunotherapy Both intrinsic and acquired resistance mechanisms, including tumor-driven evasion and compensatory upregulation of (alternative) inhibitory receptors, often limit the long-term e icacy of the current ICIs [29-31]. To address these hurdles, identifying novel immune checkpoint targets has become an interesting strategy to develop new combination therapies and overcome resistance. Novel targets include Lymphocyte activation gene 3 (LAG-3), with the ICI approved for treatment of advanced melanoma (2022)[34, 35], T cell immunoreceptor with immunoglobulin and ITIM domain (TIGIT), and VISTA[36-38]. Ongoing research and clinical trials explore the integration of these emerging ICIs with existing agents to enhance e icacy, or as salvage therapy to counteract resistance at disease progression [39, 40]. While these ICIs are primarily focused on harnessing the adaptive immune system, particularly CD8+ T cells, natural killer (NK) cells from the innate immunity also play a key role in anti-tumor immunological responses (Figure 1) [15]. Unlike T cells, NK cell’s activation does not rely on tumor antigen signaling via MHC-I, allowing them to act against tumors with low mutational burden or antigen presentation, two vulnerabilities of T-cell based immunology [41, 42]. On the other hand, NK cells do share considerable similarities with CD8+ T cells, expressing a diverse array of activating and inhibitory receptors (e.g. CD73, TIGIT, and NKG2A)[43, 44], mirroring the known T cell checkpoint concept. Beyond their cytotoxic ability, NK cells can promote the cancer-immunity cycle at multiple levels (Figure 1), including recruitment and maturation of dendritic cells (DCs) and blockage of regulatory T cell di erentiation [15, 45, 46]. Hence, targeting NKs o ers a promising avenue to broaden the scope of immunotherapy, either by directly enhancing NK cellmediated tumor clearance or by combining with existing ICIs to overcome resistance mechanisms.
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