{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T06:01:27Z","timestamp":1782280887582,"version":"3.54.5"},"posted":{"date-parts":[[2026,1,2]]},"group-title":"Immunology","reference-count":40,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T00:00:00Z","timestamp":1767312000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP200443"],"award-info":[{"award-number":["RP200443"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RR170048"],"award-info":[{"award-number":["RR170048"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"crossref","award":["RP200504"],"award-info":[{"award-number":["RP200504"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R21AI159379"],"award-info":[{"award-number":["R21AI159379"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R01HL149744"],"award-info":[{"award-number":["R01HL149744"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R01HL171622"],"award-info":[{"award-number":["R01HL171622"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["R37CA248478"],"award-info":[{"award-number":["R37CA248478"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100015326","name":"NIH Common Fund","doi-asserted-by":"crossref","award":["P30CA125123"],"award-info":[{"award-number":["P30CA125123"]}],"id":[{"id":"10.13039\/100015326","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000005","name":"US Department of Defense","doi-asserted-by":"crossref","award":["CA210552"],"award-info":[{"award-number":["CA210552"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"crossref"}]},{"name":"the Helis Medical Research Foundation"},{"name":"Samyang Biopharm Research Grant"},{"name":"BCM Department of Surgery Seed Grant"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,1,2]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>Neoadjuvant chemoimmunotherapy has improved outcomes in resectable non-small cell lung cancer (NSCLC), yet its real-world implementation is often challenged by surgical delays, immune-mediated fibrosis, and postoperative complications. Smokers with NSCLC, despite a high risk for surgical morbidity, show enhanced responses to neoadjuvant chemoimmunotherapy. This study aimed to identify smoking-associated immune cell determinants that could guide treatment strategies.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    Single-cell RNA sequencing (scRNAseq) was performed on 61 lung tissues from non-smokers and smokers to identify smoking-related immune compositions. The scRNAseq data from 19 invasive lung adenocarcinomas were used to validate their presence in the tumor-immune microenvironment. Bulk RNA sequencing data from 102 resected NSCLC and 24 NSCLC patients treated with neoadjuvant chemoimmunotherapy followed by surgery were used for\n                    <jats:italic>in silico<\/jats:italic>\n                    cellular deconvolution and outcome analyses.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Among 135 lung cellular phenotypes, two natural killer (NK) cell subsets were strongly associated with smoking and chronic obstructive pulmonary disease (COPD) severity. \u201cStress-responsive\u201d NK (NK\n                    <jats:sub>SR<\/jats:sub>\n                    ) cells exhibited immature features and cytokine-responsive features, and \u201cAdaptive and immunoregulatory NK\u201d (NK\n                    <jats:sub>AIR<\/jats:sub>\n                    ) cells showed mature features and elevated multiple immune checkpoint expression. High intratumoral NK\n                    <jats:sub>SR<\/jats:sub>\n                    cells correlated with improved survival after surgery, particularly in current smokers. Conversely, tumors with low NK\n                    <jats:sub>SR<\/jats:sub>\n                    and high NK\n                    <jats:sub>AIR<\/jats:sub>\n                    cells responded more favorably to neoadjuvant chemoimmunotherapy.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>\n                    Intratumoral NK cell phenotyping may aid in therapeutic stratification in patients with NSCLC. NK\n                    <jats:sub>SR<\/jats:sub>\n                    cell preservation predicts benefit from upfront surgery, while NK\n                    <jats:sub>AIR<\/jats:sub>\n                    cell enrichment indicates improved response to neoadjuvant chemoimmunotherapy. These NK cell profiles may help optimize treatment by balancing therapeutic benefit and risk.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Graphic Abstract<\/jats:title>\n                  <jats:fig id=\"ufig1\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"696292v1_ufig1\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Central Picture<\/jats:title>\n                  <jats:fig id=\"ufig2\" position=\"float\" orientation=\"portrait\" fig-type=\"figure\">\n                    <jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"696292v1_ufig2\" position=\"float\" orientation=\"portrait\"\/>\n                  <\/jats:fig>\n                  <jats:p>NK cell profiling for treatment stratification in resectable NSCLC<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Central Message<\/jats:title>\n                  <jats:p>Tumor-infiltrating NK cell profiling identifies distinct immune phenotypes that can inform personalized treatment strategies in resectable NSCLC.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Perspective statement<\/jats:title>\n                  <jats:p>Abundance of intratumoral stress-responsive NK cells predicts favorable outcomes after upfront surgery, whereas enrichment of adaptive and immunoregulatory NK cells suggests greater benefit from neoadjuvant chemoimmunotherapy. These findings support incorporating NK-cell profiling into preoperative decision-making to optimize therapy selection and balance risks in the high-risk surgical population.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.01.01.696292","type":"posted-content","created":{"date-parts":[[2026,1,2]],"date-time":"2026-01-02T20:40:14Z","timestamp":1767386414000},"source":"Crossref","is-referenced-by-count":0,"title":["Tumor-infiltrating natural killer cell profiling for therapeutic stratification in patients with resectable non-small cell lung cancer"],"prefix":"10.64898","author":[{"given":"Atsushi","family":"Ito","sequence":"first","affiliation":[{"name":"Systems Onco-Immunology Laboratory, David J. Sugarbaker Division of Thoracic Surgery, Michael E. 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