{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T14:51:26Z","timestamp":1790952686598,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2022,6,20]],"date-time":"2022-06-20T00:00:00Z","timestamp":1655683200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Patients with non-small cell lung cancer (NSCLC) develop bone metastasis (BoM) in more than 50% of cases during the course of the disease. This metastatic site can lead to the development of skeletal related events (SREs), such as severe pain, pathological fractures, spinal compression, and hypercalcemia, which reduce the patient\u2019s quality of life. Recently, the treatment of advanced NSCLC has radically changed due to the advent of immunotherapy. Immune checkpoint inhibitors (ICI) alone or in combination with chemotherapy have become the main therapeutic strategy for advanced or metastatic NSCLC without driver gene mutations. Since survival has increased, it has become even more important to treat bone metastasis to prevent SRE. We know that the presence of bone metastasis is a negative prognostic factor. The lower efficacy of immunotherapy treatments in BoM+ patients could be induced by the presence of a particular immunosuppressive tumor and bone microenvironment. This article reviews the most important pre-clinical and clinical scientific evidence on the reasons for this lower sensitivity to immunotherapy and the need to combine bone target therapies (BTT) with immunotherapy to improve patient outcome.<\/jats:p>","DOI":"10.3390\/ijms23126832","type":"journal-article","created":{"date-parts":[[2022,6,21]],"date-time":"2022-06-21T01:43:27Z","timestamp":1655775807000},"page":"6832","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":69,"title":["Bone Metastasis and Immune Checkpoint Inhibitors in Non-Small Cell Lung Cancer (NSCLC): Microenvironment and Possible Clinical Implications"],"prefix":"10.3390","volume":"23","author":[{"given":"Alessandro","family":"Del Conte","sequence":"first","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"De Carlo","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Bertoli","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"},{"name":"Department of Medicine (DAME), University of Udine, 33100 Udine, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0475-7399","authenticated-orcid":false,"given":"Brigida","family":"Stanzione","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4505-9650","authenticated-orcid":false,"given":"Alberto","family":"Revelant","sequence":"additional","affiliation":[{"name":"Dipartimento di Radioterapia, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manuela","family":"Bertola","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Spina","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1020-2338","authenticated-orcid":false,"given":"Alessandra","family":"Bearz","sequence":"additional","affiliation":[{"name":"Dipartimento di Oncologia Medica, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistica, 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"4592","DOI":"10.1158\/1078-0432.CCR-18-1538","article-title":"Immunotherapy in Non-Small Cell Lung Cancer: Facts and Hopes","volume":"25","author":"Doroshow","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"102031","DOI":"10.1016\/j.ctrv.2020.102031","article-title":"Real world data in the era of Immune Checkpoint Inhibitors (ICIs): Increasing evidence and future applications in lung cancer","volume":"87","author":"Pasello","year":"2020","journal-title":"Cancer Treat. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1186\/s12967-019-1847-x","article-title":"A normogram to predict survival in non-small cell lung cancer patients treated with nivolumab","volume":"17","author":"Botticelli","year":"2019","journal-title":"J. Transl. Med."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Tamiya, M., Tamiya, A., Inoue, T., Kimura, M., Kunimasa, K., Nakahama, K., Taniguchi, Y., Shiroyama, T., Isa, S.-I., and Nishino, K. (2018). Metastatic site as predictor of nivolumab efficacy in patient with advanced non-small cell lung cancer: A retrospective multicenter trial. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0192227"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1825","DOI":"10.1007\/s00262-018-2239-4","article-title":"Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC)","volume":"67","author":"Schmid","year":"2018","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"18670","DOI":"10.1038\/srep18670","article-title":"Natural History of Non-Small-Cell Lung Cancer with Bone Metastases","volume":"5","author":"Santini","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1016\/j.jbo.2012.12.004","article-title":"Incidence and Consequences of Bone Metastases in Lung Cancer Patients","volume":"2","author":"Kuchuk","year":"2013","journal-title":"J. Bone Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1053\/ctrv.2000.0210","article-title":"Metastatic bone disease: Clinical features, pathophysiology and treatment strategies","volume":"27","author":"Coleman","year":"2011","journal-title":"Cancer Treat. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.21037\/tcr-21-1507","article-title":"Prediction of overall survival of non-small cell lung cancer with metastasis: An analysis of the Surveillance, Epidemiology and End Results (SEER) database","volume":"10","author":"Shi","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/cmi.2011.47","article-title":"Bone marrow and the control of immunity","volume":"9","author":"Zhao","year":"2012","journal-title":"Cell. Mol. Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"K\u00e4hk\u00f6nen, T.E., Halleen, J.M., and Bernoulli, J. (2021). Osteoimmuno-oncology: Therapeutic opportunities targeting immune cells in bone metastasis. Cells, 10.","DOI":"10.3390\/cells10061529"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"915","DOI":"10.6004\/jnccn.2020.7668","article-title":"Bone metastases, skeletal-related events, and survival in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors","volume":"19","author":"Qin","year":"2021","journal-title":"J. Natl. Compr. Cancer Netw."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"775","DOI":"10.2217\/fon-2020-0587","article-title":"Impact of Different Patterns of Metastasis in Non-Small-Cell Lung Cancer Patients","volume":"17","author":"Bergmann","year":"2021","journal-title":"Future Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"316","DOI":"10.1186\/s40425-019-0793-8","article-title":"Bone Metastases and Immunotherapy in Patients with Advanced Non-Small Cell Lung Cancer","volume":"7","author":"Landi","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"480","DOI":"10.18632\/oncotarget.27439","article-title":"Immune system and microenvironment: Rationale for targeted cancer therapies","volume":"11","author":"Gnoni","year":"2020","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"8451","DOI":"10.1158\/0008-5472.CAN-04-1987","article-title":"Bone morrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12\/CXCR4 signal","volume":"64","author":"Zou","year":"2004","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1038\/nri3175","article-title":"Coordinated regulation of myeloid cells by tumors","volume":"12","author":"Gabrilovich","year":"2021","journal-title":"Nat. Rev. Immunol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"8970173","DOI":"10.1155\/2021\/8970173","article-title":"Immune Checkpoint inhibitor Therapy for Bone Metastases: Specific Microenvironment and Current Situation","volume":"2021","author":"Liu","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"236","DOI":"10.3389\/fendo.2019.00236","article-title":"Updates on osteoimmunology: What\u2019s new on cross-talk between bone and immune system","volume":"10","author":"Ponzetti","year":"2019","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1186\/s13046-017-0578-1","article-title":"Current concepts in bone metastasis, contemporary therapeutic strategies and ongoing clinical trial","volume":"36","author":"Gdowski","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3603","DOI":"10.1172\/JCI133334","article-title":"PD-1 blockade inhibits osteoclast formation and murine bone cancer pain","volume":"130","author":"Wang","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Mukaida, M., Zhang, D., and Sasaki, S.I. (2019). Emergence of cancer-associated fibroblast as independent cellular player in bone metastasis process. Cancer, 12.","DOI":"10.3390\/cancers12102896"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1007\/s00774-020-01182-2","article-title":"Role of RANKL in cancer development and metastasis","volume":"39","author":"Okamoto","year":"2021","journal-title":"J. Bone Miner. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"824117","DOI":"10.3389\/fimmu.2022.824117","article-title":"Role of the RANKL-RANK Axis in Immunity\u2014Implications for pathogenesis and Treatment of Bone Metastasis","volume":"13","author":"Li","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2884","DOI":"10.1038\/jid.2015.209","article-title":"Receptor activator of NF-kB ligand promotes the production of CCL17 from RANK+ M2 macrophages","volume":"135","author":"Fujimura","year":"2015","journal-title":"J. Investig. Dermatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e12125","DOI":"10.1002\/jev2.12125","article-title":"Extracellular vesicles in development of organ-specific metastasis","volume":"10","author":"Urabe","year":"2021","journal-title":"J. Extracell. Vesicles"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cell.2019.02.016","article-title":"Suppression of exosomal PD-L1 induces systemic anti-tumor immunity and memory","volume":"177","author":"Poggio","year":"2019","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1038\/s41586-018-0392-8","article-title":"Exosomal PD-L1 contributes to immunosoppresion and is associated with anti-PD-1 response","volume":"560","author":"Chen","year":"2018","journal-title":"Nature"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1593805","DOI":"10.1080\/2162402X.2019.1593805","article-title":"Circulating exosomes measure responses to therapy in head and neck cancer patients treated with cetuximab, ipilimumab, and IMRT","volume":"8","author":"Theodoraki","year":"2019","journal-title":"Osteoimmunology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"611054","DOI":"10.3389\/fonc.2020.611054","article-title":"The Potential Roles of Exosomal miR-214 in Bone Metastasis of Lung Adenocarcinoma","volume":"10","author":"Zhang","year":"2021","journal-title":"Front. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1177\/0022034516633189","article-title":"Characterization of regulatory extracellular vesicles from osteoclasts","volume":"95","author":"Huynh","year":"2016","journal-title":"J. Dent. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3170","DOI":"10.1038\/s41598-017-03460-y","article-title":"Amphiregulin contained in NSCLC-exosomes induces osteoclast differentiation though the activation of EGFR pathway","volume":"7","author":"Taverna","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e1480301","DOI":"10.1080\/2162402X.2018.1480301","article-title":"Observational study of concomitant immunotherapies and denosumab in patients with advanced melanoma or lung cancer","volume":"7","author":"Liede","year":"2018","journal-title":"Oncoimmunology"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1016\/j.lungcan.2022.03.006","article-title":"Bone metastasis attenuates efficacy of immune checkpoint inhibitors and displays \u201ccold\u201d immune characteristics in Non-small cell lung cancer","volume":"166","author":"Zhu","year":"2022","journal-title":"Lung Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2812","DOI":"10.1111\/1759-7714.13597","article-title":"Adverse impact of bone metastases on clinical outcomes of patients with advanced non-small cell lung cancer treated with immune checkpoint inhibitors","volume":"11","author":"Li","year":"2020","journal-title":"Thoracic Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.21037\/tlcr-21-1033","article-title":"Pembrolizumab monotherapy or combination therapy for bone metastases in advanced Non-Small Cell Lung Cancer","volume":"11","author":"Qiang","year":"2022","journal-title":"Transl. Lung Cancer Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"697298","DOI":"10.3389\/fimmu.2021.697298","article-title":"Immune checkpoint inhibitors with or without bone-targeted therapy in NSCLC patients with bone metastasies and prognostic significance of neutrophil-to-lymphocyte ratio","volume":"12","author":"Bongiovanni","year":"2021","journal-title":"Front. Immunol"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"871675","DOI":"10.3389\/fonc.2022.871675","article-title":"The therapeutic effect and clinical outcome of immune checkpoint inhibitors on bone metastasis in advanced non-small-cell lung cancer","volume":"12","author":"Asano","year":"2022","journal-title":"Front. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"507","DOI":"10.3389\/fcell.2020.00507","article-title":"Osteoclast Signal Transduction During Bone Metastasis Formation","volume":"8","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"488","DOI":"10.1038\/s41571-021-00499-9","article-title":"Novel approaches to target the microenvironment of bone metastasis","volume":"18","author":"Hofbauer","year":"2021","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1152\/physrev.00012.2019","article-title":"Bone metastasis: Mechanisms, therapies, and biomarkers","volume":"101","author":"Coleman","year":"2021","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"778","DOI":"10.1038\/bjc.2011.293","article-title":"Clinical evaluation of autologous gamma delta T cell-based immunotherapy for metastatic solid tumours","volume":"105","author":"Nicol","year":"2011","journal-title":"Br. J. Cancer"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1007\/s00262-011-1049-8","article-title":"Pilot trial of interleukin-2 and zoledronic acid to augment \u03b3\u03b4 T cells as treatment for patients with refractory renal cell carcinoma","volume":"60","author":"Lang","year":"2011","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_45","first-page":"37","article-title":"Induction of gamma delta T cells using zoledronate plus interleukin-2 in patients with metastatic cancer","volume":"58","author":"Nagamine","year":"2009","journal-title":"Hiroshima J. Med. Sci."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1007\/s00262-019-02353-5","article-title":"Combination of denosumab and immune checkpoint inhibition: Experience in 29 patients with metastatic melanoma and bone metastases","volume":"68","author":"Angela","year":"2019","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1097\/CMR.0000000000000459","article-title":"Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy alone versus immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1) therapy in combination with anti-RANKL denosumab in malignant melanoma: A retrospective analysis at a tertiary care center","volume":"28","author":"Afzal","year":"2018","journal-title":"Melanoma Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6832\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:35:22Z","timestamp":1760139322000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/12\/6832"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,20]]},"references-count":47,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["ijms23126832"],"URL":"https:\/\/doi.org\/10.3390\/ijms23126832","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,20]]}}}