{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T06:12:46Z","timestamp":1761027166931,"version":"build-2065373602"},"reference-count":91,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T00:00:00Z","timestamp":1761004800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Irreversible electroporation (IRE) is a relatively new, non-thermal ablation technology for cancer treatment that requires further investigation to optimize its therapeutic efficacy. To improve IRE-ablation, we developed an IRE+Combo-treatment regimen that included the Combo adjuvants poly-I:C (pIC)\/CpG, anti-PD-L1 antibody (PD-L1-Ab) and the 41BB-agonist, and investigated its anti-tumor immunity in a 3LL<jats:sub>OVA<\/jats:sub> lung cancer model. We demonstrated that inclusion of the 41BB-agonist in the IRE+Combo-ablation stimulated a more efficient CD8<jats:sup>+<\/jats:sup> T cell response (5.3%) than that observed in the absence of 41BB-agonist (3.0%) or upon IRE ablation alone (0.4%), leading to eradication of subcutaneous 3LL<jats:sub>OVA<\/jats:sub> cancer in 75% of 3LL<jats:sub>OVA<\/jats:sub>-bearing mice. We further showed that the IRE+Combo-treatment regimen resulted in the eradication of both 3LL<jats:sub>OVA<\/jats:sub> cancer and lung tumor metastases. Interestingly, our flow cytometry analyses argued that addition of the 41BB-agonist to the IRE+Combo-ablation stimulated a higher frequency of novel CD8<jats:sup>+<\/jats:sup>CD103<jats:sup>+<\/jats:sup> conventional type-1 dendritic cells (cDC1) (14.4%) in tumor-drainage lymph-nodes (TDLNs) relative to control IRE+CpG\/pIC\/PD-L1-Ab- (7.5%) and IRE- (4.0%) treatment groups. This novel cDC1 subpopulation exhibited the most robust expression of DC maturation markers and costimulatory 41BBL and 41BB of all cDC1 subsets. The 41BB-agonist also stimulated a higher frequency of 41BB<jats:sup>+<\/jats:sup>CD103<jats:sup>+<\/jats:sup>TCF-1<jats:sup>+<\/jats:sup> tissue-resident memory T (T<jats:sub>RM<\/jats:sub>) cells (14.5%) in TDLNs when compared with the two control (2.6% and 0.3%) treatment groups. Importantly, the IRE+Combo-treatment regimen was more efficient than the two control groups at converting the immunosuppressive tumor microenvironment (TME), an effect that was mitigated by reducing the frequency of inhibitory myeloid-derived suppressive cells while increasing that of immunogenic cDC1 and CD8<jats:sup>+<\/jats:sup> T cells and rescuing T cell exhaustion. Taken together, our data establish that the 41BB-agonist potentiates the efficacy of IRE+Combo-therapy for lung cancer treatment by promoting unexpected cDC1 and T<jats:sub>RM<\/jats:sub> cell responses, and emphasize the importance of targeting this promising molecular signal to improve current cancer IRE-ablation protocols.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1688281","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T05:37:42Z","timestamp":1761025062000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["The 41BB-agonist potentiates the therapeutic efficacy of a combined irreversible electroporation ablation treatment of lung cancer by promoting unexpected CD8+CD103+ cDC1 and tissue-resident memory T cell 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