Oncology:

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Dendritic cells (DCs) are specialized antigen-presenting cells that are present at low abundance in the circulation and tissues; they serve as crucial immune sentinels by continually sampling their environment, migrating to secondary lymphoid organs and shaping adaptive immune responses through antigen presentation. Owing to their ability to orchestrate tolerogenic or immunogenic responses to a specific antigen, DCs have a pivotal role in antitumour immunity and the response to immune checkpoint blockade and other immunotherapeutic approaches. The multifaceted functions of DCs are acquired through a complex, multistage process called maturation. Although the role of inflammatory triggers in driving DC maturation was established decades ago, less is known about DC maturation in non-inflammatory contexts, such as during homeostasis and in cancer. The advent of single-cell technologies has enabled an unbiased, high-dimensional characterization of various DC states, including mature DCs. This approach has clarified the molecular programmes associated with DC maturation and also revealed how cancers exploit these pathways to subvert immune surveillance. In this Review, we discuss the mechanisms by which cancer disrupts DC maturation and highlight emerging therapeutic opportunities to modulate DC states. These insights could inform the development of DC-centric immunotherapies, expanding the arsenal of strategies to enhance antitumour immunity.

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Abstract: Cytotoxic T cell immune responses against cancer crucially depend on the ability of a subtype of professional antigen-presenting cells termed conventional type 1 dendritic cells (cDC1s) to cross-present antigens. Cross-presentation comprises redirection of exogenous antigens taken from other cells to the major histocompatibility complex class I antigen-presenting machinery. In addition, once activated and having sensed viral moieties or T helper cell cooperation via CD40-CD40L interactions, cDC1s provide key co-stimulatory ligands and cytokines to mount and sustain CD8 T cell immune responses. This regulated process of cognate T cell activation is termed cross-priming. In cancer mouse models, CD8 T cell cross-priming by cDC1s is crucial for the efficacy of most, if not all, immunotherapy strategies. In patients with cancer, the presence and abundance of cDC1s in the tumour microenvironment is markedly associated with the level of T cell infiltration and responsiveness to immune checkpoint inhibitors. Therapeutic strategies to increase the numbers of cDC1s using FMS-like tyrosine kinase 3 ligand (FLT3L) and/or their activation status show evidence of efficacy in cancer mouse models and are currently being tested in initial clinical trials with promising results so far.

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Abstract: Clinically approved treatments for advanced liver cancer often lack potency because of the heterogeneous characteristics of hepatocellular carcinoma (HCC). This complexity is largely driven by context-dependent inflammatory responses brought on by diverse etiologies, such as metabolic dysfunction-associated steatohepatitis (MASH), the genetic makeup of cancer cells, and the versatile adaptability of immune cells, such as myeloid cells. In this review, we discuss the evolutionary dynamics of the immune landscape, particularly that of liver-resident Kupffer cells (KCs), TREM2, and SPP1 macrophages with an active role during liver disease progression, which eventually fuels hepatocarcinogenesis. We highlight exploitable immunomodulatory avenues amenable to mitigate both the inherent pathological characteristics of liver cancers and the associated external factors that favor malignancy, paving a roadmap toward improving the management and therapeutic outcome for patients with HCC.

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