ArticleJournal for immunotherapy of cancer2025
Synergy between TLR3-ligand and IFN-α in the transient sensitization of "Cold" tumors to PD-1 blockade and the induction of systemic immunity.
Article in Journal for immunotherapy of cancer, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
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Who cites it
2 citing papers in PubMed.
- Ecosystem-matched reprogramming of the tumor-immune microenvironment to overcome cancer immunotherapy resistance.Molecular cancer · 2026Review
- Macrophages in lung cancer: principal factors, regulatory mechanisms, and therapeutic opportunities: a narrative review.Translational lung cancer research · 2026Review
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Authors and funding
8 authors.
Funding
Abstract
backgroundProgrammed cell death protein-1 (PD-1)-blocking immune checkpoint inhibitors (ICIs) are effective against highly immunogenic "hot" tumors containing high numbers of cytotoxic T-lymphocytes (CTLs), but not against poorly immunogenic "cold" tumors. We previously reported that the combination of TLR3 agonist rintatolimod with interferon (IFN)-α selectively induces CTL-attracting chemokines (CXCL9, CXCL10, CCL5) in the tumor microenvironment (TME), but not healthy tissues, raising the possibility of their systemic application to promote local CTL attraction to TME.
methodsWe used mouse colorectal cancer (CRC) cells implanted in syngeneic mice to test the effects of chemokine modulatory regimen (CKM) in combination with PD-1 blockade applied at different schedules. Tumor-bearing mice were treated and monitored for survival. In addition, we evaluated the reliance of CKM+αPD-1 treatment on various immune cell subsets. Finally, we observed treatment-induced changes in immune markers within TME.
resultsHere, we report that both local or systemic application of CKM, a combination of rintatolimod and IFN-α, but not each of them individually, induces intratumoral CTL attractants and sensitizes PD-1-resistant MC38 and CT26 tumors to PD-1 blockade. The CKM/αPD-1 combination promotes intratumoral influx of BATF3-positive cDC1s and CTLs, inhibits tumor growth and prolongs survival, inducing cures in 20-100% of animals, depending on the tumor model and stage, and the route of delivery (local or systemic). CKM/αPD-1-treated mice develop local and systemic tumor-specific CTL responses and resistance to tumor re-challenge. The effectiveness of CKM requires its application at the time of or directly before PD-1 blockade and is strongly reduced by even a 24-hour delay in αPD-1 administration. CKM-driven intratumoral CTL accumulation and antitumor effects require host's BATF3
conclusionsThe ability of systemic CKM to eliminate the PD-1-resistance of cold tumors indicates that intratumoral CTL accumulation, rather than tumor immunogenicity, is the key factor limiting the therapeutic effectiveness of ICI. These data suggest a broad therapeutic potential of TME-reprogramming strategies.
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