{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:59:11Z","timestamp":1785473951358,"version":"3.56.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T00:00:00Z","timestamp":1785456000000},"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. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced non-small cell lung cancer (NSCLC), but clinical benefit remains heterogeneous and is not fully explained by programmed death-ligand 1 (PD-L1) expression or tumour mutational burden (TMB). We explored whether whole-exome sequencing (WES) of circulating tumour DNA (ctDNA) could identify mutational and copy-number (CN) signatures associated with outcome in advanced NSCLC treated with first-line ICI.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Baseline plasma ctDNA from 37 patients with advanced NSCLC treated with first-line ICI or chemo-ICI was analysed by WES. Single-base substitution (SBS), indel (InD) and CN signatures were inferred using COSMIC-based signature frameworks. SBS signatures reflect point mutation patterns, including clock-like processes that accumulate with age; indel signatures reflect small insertions and deletions; and CN signatures summarise structural changes such as chromosomal gains and loss of heterozygosity. Signatures were integrated with PD-L1 status, TMB, progression-free survival (PFS) and overall survival (OS). Patients were classified into four clinicogenomic groups according to PD-L1 expression and PFS.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Median PFS and OS were 9 and 20 months, respectively. Single-nucleotide-variant-derived TMB (TMB-SNV) was similar in patients with adverse and favourable outcomes, and patients with TMB-SNV &amp;gt;10 mutations\/Mb were evenly distributed between both groups. The SBS profile was mainly represented by the clock-like signatures SBS1, SBS5 and by the tobacco-like signature SBS92, whereas indel signatures were mostly represented by InD4a and InD10. CN signatures showed the most apparent separation between outcome groups. CN9 exposure, a marker of structurally unstable genomes, was higher in adverse-outcome patients and most prominent in Group 1 (PD-L1 \u226550% and adverse outcome), whilst CN21 exposure was highest in Group 4 (PD-L1 \u226550% and favourable outcome). No signature retained statistical significance after correction for multiple testing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>In this exploratory cohort, ctDNA-derived CN signatures may capture structural genomic phenotypes associated with ICI outcome beyond PD-L1 and TMB. CN9 emerged as a candidate resistance-associated signature, whereas CN21 was associated with more favourable disease control. These findings are hypothesis-generating and require validation in larger prospective cohorts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1876274","type":"journal-article","created":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T04:24:15Z","timestamp":1785471855000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["ctDNA-derived copy-number signatures associated with immune checkpoint inhibitor resistance beyond PD-L1 and TMB in advanced NSCLC"],"prefix":"10.3389","volume":"16","author":[{"given":"Pedro Gonzalez","family":"Santa-Catalina","sequence":"first","affiliation":[{"name":"Medical Oncology Department, Salamanca University Hospital","place":["Salamanca, Spain"]},{"name":"Biomedical Research Institute of Salamanca (IBSAL)","place":["Salamanca, 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