{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,19]],"date-time":"2026-06-19T04:11:24Z","timestamp":1781842284562,"version":"3.54.5"},"reference-count":23,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T00:00:00Z","timestamp":1765497600000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) are a leading immunotherapy. However, their application has not universally translated into significant benefits. A substantial number of patients either show resistance or relapse post-initial response, which emphasizes the need for more sophisticated therapeutic approaches. The drug combination is one promising route. The cancer-immunity cycle reveals the anti-tumor immune-related rate limiting steps of tumors. Theoretically, focusing on different phases of the cancer-immunity cycle can enhance therapeutic results. However, combination therapy includes a higher risk of adverse effects, which demand careful consideration.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>In this study, we combined programmed death-1 (PD-1)\/ programmed death ligand-1 (PD-L1) and cytotoxic T Lymphocyte antigen 4 (CTLA-4) inhibitors with a reduced dosage but via an intra-tumor drug delivery strategy to treat recurrent\/refractory (R\/R) advanced solid tumors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Herein, we report four patients with favorable outcomes (complete response for more than 2 years). In our cases, most TRAEs are of grade 1-2.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Intratumoral co-delivery of PD-1\/PD-L1 and CTLA-4 inhibitors with reduced dosage shows promising efficacy and safety in R\/R advanced solid tumors. In addition to reducing drug-related adverse events, this technology has advantages in activating tumor immunity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Clinical Trial Registration<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link>https:\/\/clinicaltrials.gov\/<\/jats:ext-link>\n                      , identifier: NCT03755739.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2025.1669924","type":"journal-article","created":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T05:14:59Z","timestamp":1765516499000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Intratumoral delivery of PD-1\/PD-L1 and CTLA-4 inhibitors for recurrent\/refractory solid tumors: a proof-of-concept treatment 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