Table 2.

Key preclinical studies demonstrating dependence on cDC1 for successful immunotherapy

Immunotherapy approachGenetic model utilizedTumor model utilizedKey findingsReference
ICB 
αCXCR4 + αPD-1 IgG combination Batf3−/− C57BL/6J Orthotopic (HCA-1) and autochthonous HCC models cDC1 prevalence and proximity to CD8+ T cells increased following combination therapy. Combination therapy effectiveness was compromised in KO mice Morita et al. (2025)  
αPD-L1 IgG Chimeric mice: BM from CD11c-DTR-eGFP mice mixed with WT or Batf3−/− mice B16-SIY and MC8-SIY SC models Presence of cDC1s in the TME expressing the costimulatory molecule 4-1BBL required for optimal response to anti-PD-1 blockade Ziblat et al. (2024)  
αPD-1 + α4-1BB IgG combination C57BL/6 XCR1DTRVenus
B6.129S(C)-Batf3tm1Kmm/J 
MC38 SC model cDC1 depletion impaired therapeutic efficacy associated with reduced intratumoral T cell infiltration Teijeira et al. (2022)  
αPD-1 + αCTLA4 IgG alone and in combination C57BL/6 Xcr1DTRVenus E0771 SC model cDC1 depletion impaired therapeutic efficacy Teijeira et al. (2022)  
αCTLA4 IgG Batf3−/−
C57BL/6 Xcr1DTRVenus 
Orthotopic MOSC1 tongue tumor model αCTLA4-targeted therapy resulted in increase of cDC1s in tdLN. Therapeutic response was diminished in Batf3−/− mice
Early depletion of cDC1s relative to treatment impairs response, while later depletion had less impairment on therapeutic efficacy 
Saddawi-Konefka et al. (2022)  
αPD-1 IgG + CCL7 combination N/A Autochthonous KrasLSL−G12D/+Tp53fl/fl (KP) and the KrasLSL−G12D/+Lkb1fl/fl (KL) NSCLC mouse models Combined treatment prolonged survival of mice compared with untreated and PD-1 treatment alone. Therapeutic efficacy was associated with increased infiltration of cDC1s and CD8+ T cells Zhang et al. (2020)  
αPD-L1 IgG CD11c-Cre; Pdl1^fl/f and Batf3−/− C57BL/6J MC38 and EG.7 SC models PD-L1 expression on DCs essential for response to αPD-L1–targeted therapy. Efficacy of αPD-L1–targeted therapy was diminished in Batf3−/−mice. cDC1s upregulate PD-L1 upon antigen uptake driven by IFNγ signaling Peng et al. (2020)  
Clec9a-Cre Cd274fl/fl
C57BL/6N mice (not cDC1 specific—all mature DCs) 
PD-L1–deficient and PD-L1–sufficient MC38, and HEPA1-6.X1.1 SC models Deletion of PD-L1 expression on DCs, and not macrophages, leads to restriction of tumor growth and enhanced antitumor T cell responses.
DCs identified as key mediators of PD-1:PD-L1 axis 
Oh et al. (2020)  
αPD-1 + α4-1BB IgG Batf3−/− BALB/C Orthotopic 4T1.2 mammary carcinoma model Adjuvant or neoadjuvant immunotherapy efficacy was diminished in Batf3−/− mice associated with reduced CD8+ T cell priming Liu et al. (2019)  
αPD-1 IgG Zbtb46-Dtr chimera models MC38 SC model Efficacy of αPD-1–targeted therapy was impaired when DCs were depleted or when IL-12 was neutralized. Authors demonstrate a role for IL-12+ cDC1s for optimal therapeutic response Garris et al. (2018)  
αPD-L1 IgG Batf3−/− C57BL/6J B16 SC models Efficacy of αPD-L1–targeted therapy was diminished in Batf3−/−mice. CD103+ DCs were required to induce treatment-induced antitumor immunity. Therapeutic synergy was observed between systemic FLT3L, αPD-L1 IgG, and intratumoral poly I:C treatment Salmon et al. (2016)  
αPD-1 + α4-1BB IgG alone and in combination
α4-1BB IgG + IL-12
αPD-1 or α4-1BB IgG in combination with FLT3L and poly-ICLC 
Batf3−/− C57BL/6J MC38, MC38-OVA, and B16-OVA SC models Efficacy of each immunotherapeutic approach trialed was diminished in Batf3−/− mice associated with the absence of CD8+ T cell priming Sánchez-Paulete et al. (2016)  
Costimulatory agonist therapy 
Systemic α4-1BB IgG in combination with intratumoral HMGN1 (TLR4 agonist) and 3M-052 (TLR7/8 agonist) ISV Batf3−/− C57BL/6J MC38 SC models Combination therapy efficacy was diminished in Batf3−/− mice associated with lower secretion of IFNγ by T cells in treated mice Wang et al. (2025)  
αCD40 IgG + systemic recombinant FLT3L protein C57BL/6 Xcr1DTRVenus Orthotopic KP2 OVA–expressing models Intratumoral expansion of total CD8+ T cells, IFNγ+ CD8+ T cells, and therapeutic benefit following treatment was diminished in the absence of cDC1s. Additionally, cDC1 numbers in TME following treatment may be sustained via IFNγ signaling Hogg et al. (2025)  
αCD40 IgG + systemic recombinant FLT3L protein Batf3−/− C57BL/6J WT- and Mlh1-deficient KP NSCLC SC models Therapeutic strategy to boost DC prevalence and activation via FLT3L and αCD40 IgG delivery exhibits diminished efficacy in cDC1-deficient mice, associated with diminished CD8+ T cell infiltration into tumor López et al. (2024)  
Bispecific antibodies targeting CD40 and DC/cDC1 cell surface markers Batf3−/− C57BL/6J
Xcr1-iDTR 
MC38 SC, B16-OVA SC, and MCA-205 SC models cDC1s are responsible for therapeutic efficacy of therapy but are not implicated in toxicity
αCD40-targeted treatment does not induce tumor-specific CD8+ T cells, or therapeutic efficacy in Batf3−/− mice 
Salomon et al. (2022)  
N/A Xcr1Cre/+Cd40fl/fl (cDC1-specific CD40 deletion) 1956-mOVA fibrosarcoma SC model Loss of CD40 signaling in cDC1 diminishes (1) endogenous antitumor CD8+ T cell responses due to lack of cDC1 licensing, (2) early CD4+ T cell activation Ferris et al. (2020)  
αCD40 IgG + αPD-1/CTLA4 IgG B6.129S(C)-Batf3tm1Kmm/J PDA SC model Therapeutic efficacy was ablated in Batf3−/− mice Morrison et al. (2020)  
αCD40 IgG + gemcitabine/Nab-paclitaxel chemotherapy Batf3−/− C57BL/6J PDA SC model Therapeutic efficacy was diminished in Batf3−/− mice Byrne and Vonderheide (2016)  
Oncolytic virus therapy 
Oral reovirus therapy B6.129S(C)-Batf3tm1Kmm/J CT26 SC models Demonstrates the efficacy of oral delivery of oncolytic virus for, with effects dependent on cDC1s, type I IFN signaling and CD8+ T cells. Oral delivery was not therapeutically effective in cDC1-deficient mice Lee et al. (2024b)  
Intratumoral recombinant FLT3L and oncolytic NDV delivery Batf3−/− BALB/C A20 SC models Therapeutic synergy observed between intratumoral recombinant FLT3L delivery and intratumoral NDV delivery. Synergistic effects absent in cDC1-deficient mice
Lack of therapeutic efficacy in cDC1-deficient mice associated with lack of induction of tumor-specific T cells 
Svensson-Arvelund et al. (2022)  
Intratumoral delivery of heat-inactivated or live oncolytic vaccinia virus engineered to express GM-CSF Batf3−/− C57BL/6J B16 ID models cDC1s required for antitumor effects of both live and inactivated oncolytic virus delivery Wang et al. (2021)  
Intratumoral delivery of inactivated modified vaccine virus Ankara Batf3−/− C57BL/6J B16 ID models Therapeutic efficacy was dependent on cDC1s and additionally STING signaling in host. cDC1s required for induction of tumor-specific CD8+ T cell responses following therapy Dai et al. (2017)  
ACT 
ACT cells expressing XCL1, FLT3L, or combination of both (ACT-FX) Batf3−/−C57BL/6N B16-OVA and MC-38 OVA SC models cDC1s required for efficacy of WT ACT or XCL1-expressing ACT. Additionally, ACT-FX were most effective at controlling tumor growth associated with enhanced DC:T cell interactions in the TME Xiao et al. (2025)  
ACT of OT-I cells XCR1-DTR-Venus C57BL/6J B16-OVA and MC-38 SC models cDC1 depletion impaired the efficacy of ACT utilizing OT-I cells associated with decreased intratumoral infiltration, decreased stemness, and increased expression of exhaustion markers Teijeira et al. (2022)  
ACT of TYRP1-targeted CAR-T cells alone or in therapeutic combination with STING agonism Batf3−/− B16 SC models cDC1 depletion impaired the efficacy of CAR-T therapy ± STING agonism associated with a loss of epitope spreading and associated expansion of tumor-directed endogenous CD8+ T cell responses Conde et al. (2021)  
ACT of CAR-T cells expressing FLT3L in combination with poly I:C treatment N/A E0771-OVA-Her2 & MC38-Her2 SC models CAR-T cells engineered to express FLT3L, given alongside poly I:C and α4-1BB IgG, promoted more effective tumor control, associated with expansion of cDC1, cDC2 populations in the TME and induction of epitope spreading in treated mice Lai et al. (2020)  
ACT of CD40L-overexpressing CAR-T cells Batf3−/− BALB/C Systemic A20 lymphoma model Therapeutic efficacy diminished in Batf3−/− mice. Differentiation and expansion of cDC1s in the TME noted in response to ACT Kuhn et al. (2020)  
ACT of Pmel-1 CD8+ T cells alone and in combination with hgp100 peptide vaccination Batf3−/− C57BL/6J B16 SC model Expansion of transferred cells was absent in Batf3−/− mice. Utilizing bone chimera models, authors confirm role for CD40 and CD70 signaling in host BATF3-reliant cells for ACT expansion and efficacy Oba et al. (2020)  
ACT of CD8+ T cells isolated from matched 2C donor mice and subsequently activated ex vivo CD11c-DTR/Batf3−/− Autochthonous BP, BP-SIY, BPC-SIY melanoma models CD103+ BATF3-dependent cells in the TME produce CXCL9/10 that promote intratumoral infiltration of transferred cells Spranger et al. (2017)  
ACT of OT-I cells XCR1-DTR:Ccr7−/− mixed BM chimeras B78ChOVA SC model CCR7-dependent migration of CD103+ DCs is required in the dLN to effectively prime previously transferred antitumor T cells Roberts et al. (2016)  
ACT of OT-I cells FTY720-treated zDC-DTR mice EG7.1 SC model CD103+ DCs in tumor are required for antitumor effect of ACT Broz et al. (2014)  
cDC1-based vaccination 
Intratumoral vaccination with peptide-loaded/activated CD34+ HSC-derived human cDC1s in combination with systemic anti–PD-1 IgG N/A SC humanized A375 melanoma model Establishes the therapeutic feasibility and efficacy of a scalable, serum-free platform for generation of bona fide cDC1 from CD34+ progenitors. Intratumoral delivery of activated, antigen-loaded cDC1s combined with anti-PD-1 treatment reduced tumor growth in a humanized melanoma model Balan et al. (2025)  
Vaccination with splenic cDC1 or cDC2 loaded with tumor cell lysate via UV-irradiated tumor cells and stimulated with CpG ex vivo N/A SC B16-OVA and MC38 cDC1 vaccination more effective than cDC2 based in delaying tumor growth/prolonging survival and induction of Th1 and CD8+ T cell effector and memory responses Heras-Murillo et al. (2025)  
Intratumoral cDC1 vaccination in combination with αPD-1 IgG. XCR1+ cDC1s isolated from the spleen of mice harboring B16-FLT3L tumors were utilized. cDC1s were treated with poly I:C and tumor antigen peptides prior to delivery N/A Orthotopic MOC1esc1 (HNSCC model) Intratumoral cDC1 vaccination restored αPD-1 responsiveness associated with expansion of tumor antigen–specific response and intratumoral infiltration Saito et al. (2024)  
Antigen agonistic approach involving intratumoral vaccination with cDC1, cDC2, or GM-CSF/IL-4–cultured DCs N/A 1956 mOVA SC model cDC1-based vaccination outperformed cDC2 or GM-CSF/IL-4 DCs in terms of tumor control and induction of tumor-specific CD8+ T cell responses. Vaccination was only effective via intratumoral and not intravenous route. cDC1-based vaccination was not reliant on the presence of host cDC1s Ferris et al. (2022)  
Intratumoral delivery of autologous CD141+ combined with αPD-1 IgG in humanized mouse model N/A Humanized mouse model—LM-MEL28 human melanoma cell line Vaccination of humanized mouse autologous CD141+ DCs (previously activated with poly I:C) synergizes with αPD-1 therapy Lee et al. (2021)  
Vaccination with in vitro generated, tumor antigen–loaded, and poly I:C-activated CD103+ DCs alone and in combination with αPD-1 or αCTLA4 IgG N/A B16 and K7M3 (osteosarcoma) SC and metastatic models CD103+ DC-based vaccination outperformed moDC-based vaccination in delaying tumor growth and inducing tumor-specific T cell responses. CD103+ cDC1 vaccination exhibited therapeutic synergy with ICB approaches Zhou et al. (2020)  
Vaccination with splenic cDC1 loaded with tumor cell lysate via UV-irradiated tumor cells and stimulated with poly I:C ex vivo N/A B16, B16-OVA, and MC38 SC models First study to demonstrate the efficacy of cDC1-based cancer vaccination. Vaccination with dead tumor cell–loaded cDC1s promoted therapeutic efficacy alone and synergized with PD-1–directed ICB Wculek et al. (2019)  
Vaccination with DCs isolated from LLC-OVA tumors: cDC2 (MHC class II+ CD11c+ CD64 CD24 CD11b+ Ly6Clo), cDC1 (MHC class II+, CD11c+ CD64 CD24+ CD11bloN/A B16-OVA, LLC-OVA SC models cDC1-based vaccination promoted strong induction of antitumor cytotoxic CD8+ T cells
cDC1-based vaccination outperformed cDC2-based approaches in the B16-OVA tumor model
cDC2-based vaccination outperformed cDC1-based approaches in the LLC-OVA tumor model, with authors hypothesizing role of MDSCs and TAMs in TME mediating lack of cDC1 efficacy 
Laoui et al. (2016)  

ACT, adoptive cell therapy; TME, tumor microenvironment; NSCLC, non–small-cell lung cancer; BM, bone marrow; SC, subcutaneous; PDA, pancreatic ductal adenocarcinoma; NDV, Newcastle disease virus.

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