Panel A: Immune checkpoint blockade (ICB) shows how anti-CTLA-4 and anti-PD-1/PD-L1 therapies rely on cDC1 cells to activate and expand CD8 positive T cells. In a cDC1-deficient host, CD8 positive T cell priming is reduced, weakening the response. Panel B: Costimulatory agonist therapy illustrates how CD40 agonism activates cDC1 cells to drive CD8 positive T cell expansion and tumor infiltration. In a cDC1-deficient host, the response to CD40 targeted therapy is impaired. Panel C: Adoptive cell transfer (ACT) demonstrates how cDC1 cells support the recruitment and expansion of transferred T cells. In a cDC1-deficient host, transferred cells show reduced expansion and increased exhaustion. Panel D: Oncolytic virus therapy shows how viruses induce tumor lysis, releasing antigens that activate cDC1 cells. In a cDC1-deficient host, the response to oncolytic virus therapy is compromised. Panel E: cDC1 cell-based vaccination indicates that ex vivo generated/activated cDC1 vaccines promote anti-tumor T cell responses and synergize with ICB. cDC2 or moDC-based approaches induce weaker T cell responses.
cDC1-dependent mechanisms that support efficacy across major immunotherapy classes. For each therapy class, the left side shows an immunocompetent setting with functional cDC1, and the right side shows a cDC1-deficient host summarizing common phenotypes when cDC1s are absent. (A) ICB. Anti-PD-1/anti-PD-L1 and anti-CTLA-4 responses rely on cDC1-mediated cross-presentation and continued restimulation of tumor-reactive CD8+ T cells. cDC1-derived mediators including IL-12 and cDC1-CD8+ T cell proximity associate with response, and increasing cDC1 abundance/activation can potentiate benefit. cDC1 deficiency reduces CD8+ T cell priming and weakens responses to ICB. (B) Costimulatory agonist therapy. CD40 agonism activates and licenses cDC1 to drive CD8+ T cell expansion and tumor infiltration. Antitumor activity is cDC1-dependent, while toxicities reported for CD40 agonists are not. (C) ACT. ACT (including CAR-T and other transferred T cell therapeutics) benefits from cDC1-mediated chemokine support (e.g., CXCL9/10) that enhances recruitment of transferred cells to the TME, and for the induction of epitope spreading. In cDC1-deficient settings, transferred cells show reduced expansion/infiltration, increased exhaustion, and diminished epitope spreading. (D) Oncolytic virus therapy. Oncolytic viruses induce tumor lysis with release of antigen and immunostimulatory nucleic acids that promote type I IFN release and activation of cDC1, enabling cross-priming in tdLN and subsequent CD8+ T cell expansion and accumulation in tumors. cDC1 deficiency compromises responses to live or inactivated viruses and limits intratumoral CD8+ T cell expansion/infiltration. (E) cDC1-based vaccination. Ex vivo–generated/activated cDC1 vaccines (delivered intratumorally) promote antitumor effector and memory T cell responses and synergize with ICB. cDC2- or moDC-based approaches induce weaker T cell responses and reduced therapeutic efficacy.