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The CD47–signal regulatory protein α (SIRPα) axis inhibits dendritic cell (DC) phagocytosis and contributes to immune evasion. However, the behaviour of DCs and the potential crosstalk between DCs and natural killer (NK) cells in the hepatocellular carcinoma (HCC) microenvironment after CD47 blockade remain unclear. The infiltration of CD103+ DCs and NK cells were analysed by immunohistochemistry and immunofluorescence in both human and murine HCC specimens. An orthotopic liver tumour model was used to evaluate the function of the CD103+ DC–NK cell axis after CD47 blockade in vivo in wild-type, Rag1 -/- , Batf3 -/- , and STING1 -/- mice. Phagocytosis assays were performed in CD103+ DC and HCC cell lines. CD103+ DC-derived cytokines were analysed by chemokine array. Spleen-derived NK cells in C57BL/6J mice were used to evaluate cytotoxic functions in vitro. Higher CD47 expression was associated with worse prognosis in patients with HCC. CD47 blockade enhanced antitumour efficacy by stimulating the CD103+ DC–NK cell axis. The hypoxic microenvironment promoted CD47 blockade-induced tumour DNA phagocytosis by CD103+ DCs. By releasing IL-12 and CXCL9, activated CD103+ DCs induced the recruitment of NK cells with upregulated expression of granzyme B, NKG2D, interferon-γ, and tumour necrosis factor-α and downregulated expression of NKG2A. The antitumour effects of CD47 blockade could be abolished by cyclic GMP–AMP synthase (cGAS)–STING pathway inhibition. In addition to the classical DC–T cell axis, CD47 blockade significantly enhanced the ability of CD103+ DCs to take up tumour DNA, resulting in the stimulation of the cGAS–STING pathway, which promoted the infiltration and activation of NK cells in liver cancer. Hypoxia (low oxygen levels) is prevalent in the hepatocellular carcinoma microenvironment and promotes the phagocytosis (ingestion and elimination) of tumour DNA by CD103+ dendritic cells (a type of immune cell). Blockade of the cell surface protein CD47 resulted in activation of CD103+ dendritic cells which led to the recruitment and activation of natural killer cells (a different immune cell). When activated, these cells exhibit an antitumour effect. [Display omitted] • CD47-blockade enhances antitumour efficacy by triggering the CD103+ DC–NK cell axis in HCC. • CD47 blockade promotes CD103+ DC phagocytosis in synergy with hypoxia. • CD103+ DC-derived IL-12 and CXCL9 are responsible for NK cell activation and recruitment. • The intrinsic activation of the cGAS–STING pathway of CD103+ DC facilitates NK cell activation and recruitment in CD47 blockade. [ABSTRACT FROM AUTHOR]

CD103+ DC is crucial for antitumor immune response. As a promising local therapy on cancers, nanosecond pulsed electric field (nsPEF) has been widely reported to stimulate anti-tumor immune response, but the underlying relationship between intratumoral CD103+ DC and nsPEF treatment remains enigmatic. Here, we focused on the behavior of CD103+ DC in response to nsPEF treatment and explored the underlying mechanism. We found that the nsPEF treatment led to the activation and accumulation of CD103+ DC in tumor. Depletion of CD103+ DC via Batf3−/− mice demonstrated CD103+ DC was necessary for intratumoral CD8+ T cell infiltration and activation in response to nsPEF treatment. Notably, NK cells recruited CD103+ DC into nsPEF-treated tumor through CCL5. Inflammatory array revealed CD103+ DC-derived IL-12 mediated the CCL5 secretion in NK cells. In addition, the boosted activation and infiltration of intratumoral CD103+ DC were abolished by cGAS-STING pathway inhibition, following IL-12 and CCL5 decreasing. Furthermore, nsPEF treatment promoting CD103+ DC-mediated antitumor response enhanced the effects of CD47 blockade strategy. Together, this study uncovers an unprecedented role for CD103+ DC in nsPEF treatment-elicited antitumor immune response and elucidates the underlying mechanisms. • CD103+ DC is necessary for antitumor immune response induced by nsPEF treatment. • NsPEF treatment leads to activation of intratumoral CD103+ DC. • NsPEF treatment induces the recruitment of CD103+ DC via IL12-NK-CCL5 axis. • CGAS-STING pathway controls activation and recruitment of CD103+ DC. • CD47 blockade promotes nsPEF-mediated activation and recruitment of CD103+ DC. [ABSTRACT FROM AUTHOR]