The discovery of dendritic cells (DC) is a key breakthrough in the field of immunology (Steinman & Cohn, 1973). DC play an important role in the induction of protective adaptive immunity, including the antitumor T-cell response. Immature DC and DC progenitors can be recruited into the TME, where progenitors can differentiate into DC (Diao et al., 2010, Salmon, 2016), and depending on the molecular signals they receive, DC can be successfully or inefficiently activated. Migratory DC of the classical DC (cDC) type have the unique ability to transport tumor-associated antigens (TAAs) from the tumor microenvironment (TME) to the tumor-draining lymph nodes (TDLN) where they can initiate tumor-specific T-cell responses (Broz et al., 2014, Roberts et al., 2016). Primed T-cells then enter the TME to directly kill tumor cells or to modulate the state of resident immune cells, which may eventually lead to tumor control (Chen & Mellman, 2013). Type 1 cDC (cDC1) can be licensed by CD4+ T-cells to mature, optimizing antigen presentation, costimulatory and other function that foster clonal expansion, effector- and memory differentiation of T-cells in both TDLN and TME (Borst et al., 2018, Ferris et al., 2020, Lei, 2023). A recent study supports the importance of the interaction between tumor-infiltrating DC and CD4+ T-cells via MHC-II-restricted antigen presentation in preventing tumor-reactive CD8+ T-cell dysfunction (Kilian et al., 2023). DC provide co-stimulatory signals in the TME that are crucial for further effector differentiation of TCF1+ stem-like CD8+ T-cell primed in TDLN (Prokhnevska et al., 2023). DC not only help maintain a TCF1+ stem-like CD8+ T-cell reservoir in TDLN (Schenkel et al., 2021) but also shape T-cell heterogeneity (Burger et al., 2021) in specific niches in the TME, such as specific DC-rich niches (Duraiswamy et al., 2021, Jansen et al., 2019), tertiary lymphoid structures (TLS) (Meylan et al., 2022) or “stem-immunity hubs” (Chen et al., 2023). Patients with progressive cancer lack these “immune niches” (Jansen et al., 2019) (non-inflamed tumors), suggesting that these “immune” niches in the TME (inflamed tumors) are one of the key determinants of cancer immune control.

While being pivotal for the induction of antitumor immunity, DC also have an essential function in the maintenance of immune tolerance (Steinman, 2012). This task is accomplished through multiple immune checks and balances (Pardoll, 2012), which include stimulatory immune checkpoint proteins (ICPs) that promote protective immunity and inhibitory ICPs that prevent immunopathology and autoimmunity (Webster, 2014). ICPs regulate diverse immune functions in a context-dependent manner. In the TME, tumor cells via various factors and signal pathways exert suppressive properties which contribute to the abnormal regulation of DC. The key features of the negative regulation on DC functions (Wculek et al., 2020) by tumors include inhibiting DC differentiation/recruitment/maturation, interfering with TAA cross-presentation, modifying DC metabolism and compromising DC viability. DC can be polarized into immunosuppressive/tolerogenic states, that are incapable of migrating to the TDLN and have no ability to (cross) present TAAs, resulting in tumor growth and disease progression because of insufficient DC-mediated antitumor immunity. T-cell based tumor immunity is compromised when cDC are absent in the TME and/or cDC are not able to migrate to the TDLN (Broz et al., 2014, Roberts et al., 2016, Spranger et al., 2017). Thus, better understanding of ICP functions on DC is crucial for strategies to reinvigorate impaired DC functions in cancer patients, which will potentially lead to conversion of the TME from a non-inflamed to an inflamed state.

Using blocking antibodies against inhibitory ICPs, an approach called immune checkpoint blockade (ICB), is a key strategy in immune-oncology research and some approaches have successfully been translated to the clinic (Gaikwad, Agrawal, Kaushik, Ramachandran, & Srivastava, 2022). However, the response rate for ICB and agonists of stimulatory ICPs is still unsatisfactory (Mayes et al., 2018, Ribas and Wolchok, 2018). Until now, efforts have been made mainly on targeting T-cells, which are critical for successful immunotherapies (Pardoll, 2012, Wei et al., 2018). Innate ICP biology is a relatively new area of research and increasing evidence indicates that therapeutic intervention of ICPs on DC contributes to the efficacy of checkpoint therapies (Mayoux, 2020, Sharpe and Pauken, 2018). In this review, we discuss DC functions in tumor immunology and elaborate therapeutic potential of DC-intrinsic ICP currently under investigation for in the cancer context.