{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,3]],"date-time":"2026-07-03T11:12:40Z","timestamp":1783077160711,"version":"3.54.6"},"reference-count":58,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,3,8]],"date-time":"2025-03-08T00:00:00Z","timestamp":1741392000000},"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>Treatment of resectable advanced-stage melanoma with neoadjuvant immunotherapy is rapidly becoming the new standard of care due to significant improvements in event-free survival (EFS) compared to surgery first followed by immunotherapy. The level of responsiveness seen in patients receiving immune checkpoint inhibitors (ICIs) must be mechanistically understood not only for the standardization of treatment but also to advance the novel concept of personalized cancer immunotherapy. This review aims to elucidate markers of the tumor microenvironment (TME) and blood that can predict treatment outcome. Interestingly, the canonical proteins involved in the molecular interactions that immunotherapies aim to disrupt have not been consistent indicators of treatment response, which amplifies the necessity for further research on the predictive model. Other major discussions surrounding neoadjuvant therapy involve the higher-level investigation of ICI efficacy due to the ability to examine a post-treatment tumor molecularly and pathologically, which this review will also cover. As neoadjuvant ICI becomes the standard of care in advanced melanoma treatment, further research aiming to identify more predictive biomarkers of treatment response to advance medical decision-making and patient care should continue to be sought after.<\/jats:p>","DOI":"10.3390\/ijms26062427","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T06:59:59Z","timestamp":1741589999000},"page":"2427","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Opportunities for Discovery Using Neoadjuvant Immune Checkpoint Blockade in Melanoma"],"prefix":"10.3390","volume":"26","author":[{"given":"Uma","family":"Nair","sequence":"first","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9356-5704","authenticated-orcid":false,"given":"Emily","family":"Rakestraw","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6387-9030","authenticated-orcid":false,"given":"Georgia M.","family":"Beasley","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret H.","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"Department of Surgery, Duke University, Durham, NC 27710, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"782","DOI":"10.1002\/jso.26229","article-title":"Neoadjuvant immunotherapy for melanoma","volume":"123","author":"Lee","year":"2021","journal-title":"J. Surg. Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1038\/s41591-018-0250-0","article-title":"Is earlier better for melanoma checkpoint blockade?","volume":"24","author":"Robert","year":"2018","journal-title":"Nat. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.1038\/s41591-018-0198-0","article-title":"Neoadjuvant versus adjuvant ipilimumab plus nivolumab in macroscopic stage III melanoma","volume":"24","author":"Blank","year":"2018","journal-title":"Nat. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2521","DOI":"10.1056\/NEJMoa1503093","article-title":"Pembrolizumab versus Ipilimumab in Advanced Melanoma","volume":"372","author":"Robert","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1535","DOI":"10.1056\/NEJMoa1910836","article-title":"Five-Year Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma","volume":"381","author":"Larkin","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e000398","DOI":"10.1136\/jitc-2019-000398","article-title":"Defining tumor resistance to PD-1 pathway blockade: Recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce","volume":"8","author":"Kluger","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"5191","DOI":"10.1158\/1078-0432.CCR-18-1550","article-title":"Immunotherapy of Melanoma: Facts and Hopes","volume":"25","author":"Weiss","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1200\/JCO.2017.72.2850","article-title":"Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study","volume":"36","author":"Callahan","year":"2018","journal-title":"J. Clin. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eaar3593","DOI":"10.1126\/science.aar3593","article-title":"Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy","volume":"362","author":"Cristescu","year":"2018","journal-title":"Science"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1038\/s41591-018-0136-1","article-title":"Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response","volume":"24","author":"Jiang","year":"2018","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"568","DOI":"10.1038\/nature13954","article-title":"PD-1 blockade induces responses by inhibiting adaptive immune resistance","volume":"515","author":"Tumeh","year":"2014","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1016\/j.cell.2017.07.024","article-title":"Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade","volume":"170","author":"Wei","year":"2017","journal-title":"Cell"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.clindermatol.2012.08.017","article-title":"Immunology of melanoma","volume":"31","author":"Mukherji","year":"2013","journal-title":"Clin. Dermatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1200\/JCO.2011.37.8539","article-title":"Tumor-infiltrating lymphocyte grade is an independent predictor of sentinel lymph node status and survival in patients with cutaneous melanoma","volume":"30","author":"Azimi","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/B978-0-12-394383-5.00011-4","article-title":"The immune system\u2014A hidden treasure for biomarker discovery in cutaneous melanoma","volume":"58","author":"Neagu","year":"2012","journal-title":"Adv. Clin. Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1093\/jnci\/81.24.1893","article-title":"Model Predicting Survival in Stage I Melanoma Based on Tumor Progression","volume":"81","author":"Clark","year":"1989","journal-title":"JNCI J. Natl. Cancer Inst."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"3447","DOI":"10.1172\/JCI87324","article-title":"Tumor immune profiling predicts response to anti-PD-1 therapy in human melanoma","volume":"126","author":"Daud","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2724","DOI":"10.1038\/s41467-018-05072-0","article-title":"Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors","volume":"9","author":"Duhen","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100127","DOI":"10.1016\/j.xcrm.2020.100127","article-title":"CD103+ CD8+ T(RM) Cells Accumulate in Tumors of Anti-PD-1-Responder Lung Cancer Patients and Are Tumor-Reactive Lymphocytes Enriched with Tc17","volume":"1","author":"Corgnac","year":"2020","journal-title":"Cell Rep. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3036","DOI":"10.1158\/1078-0432.CCR-17-2257","article-title":"CD103+ Tumor-Resident CD8+ T Cells Are Associated with Improved Survival in Immunotherapy-Na\u00efve Melanoma Patients and Expand Significantly During Anti-PD-1 Treatment","volume":"24","author":"Edwards","year":"2018","journal-title":"Clin. Cancer Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.immuni.2022.12.001","article-title":"The ectonucleotidase CD39 identifies tumor-reactive CD8+ T cells predictive of immune checkpoint blockade efficacy in human lung cancer","volume":"56","author":"Chow","year":"2023","journal-title":"Immunity"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"794","DOI":"10.1038\/s43018-021-00232-6","article-title":"Mature tertiary lymphoid structures predict immune checkpoint inhibitor efficacy in solid tumors independently of PD-L1 expression","volume":"2","author":"Vanhersecke","year":"2021","journal-title":"Nat. Cancer"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1038\/s41586-019-1914-8","article-title":"Tertiary lymphoid structures improve immunotherapy and survival in melanoma","volume":"577","author":"Cabrita","year":"2020","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1186\/s40425-019-0770-2","article-title":"Mechanisms regulating PD-L1 expression on tumor and immune cells","volume":"7","author":"Chen","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1111\/j.1600-065X.2010.00923.x","article-title":"The PD-1 pathway in tolerance and autoimmunity","volume":"236","author":"Francisco","year":"2010","journal-title":"Immunol. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1146\/annurev.immunol.26.021607.090331","article-title":"PD-1 and its ligands in tolerance and immunity","volume":"26","author":"Keir","year":"2008","journal-title":"Annu. Rev. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1038\/sj.bjc.6603763","article-title":"Mechanisms of local immunosuppression in cutaneous melanoma","volume":"96","author":"Polak","year":"2007","journal-title":"Br. J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1200\/JCO.2016.67.2477","article-title":"Programmed Death-Ligand 1 Expression and Response to the Anti-Programmed Death 1 Antibody Pembrolizumab in Melanoma","volume":"34","author":"Daud","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1016\/S1470-2045(17)30065-7","article-title":"Nivolumab in metastatic urothelial carcinoma after platinum therapy (CheckMate 275): A multicentre, single-arm, phase 2 trial","volume":"18","author":"Sharma","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1038\/nature14011","article-title":"Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients","volume":"515","author":"Herbst","year":"2014","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2143","DOI":"10.1002\/cncr.30444","article-title":"Immune and molecular correlates in melanoma treated with immune checkpoint blockade","volume":"123","author":"Byrne","year":"2017","journal-title":"Cancer"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1056\/NEJMoa1604958","article-title":"Mutations Associated with Acquired Resistance to PD-1 Blockade in Melanoma","volume":"375","author":"Zaretsky","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1038\/labinvest.2017.64","article-title":"Melanoma subtypes demonstrate distinct PD-L1 expression profiles","volume":"97","author":"Kaunitz","year":"2017","journal-title":"Lab. Investig."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1422","DOI":"10.1158\/2159-8290.CD-18-1259","article-title":"The Mechanism of Anti-PD-L1 Antibody Efficacy against PD-L1-Negative Tumors Identifies NK Cells Expressing PD-L1 as a Cytolytic Effector","volume":"9","author":"Dong","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5024","DOI":"10.1158\/1078-0432.CCR-16-0698","article-title":"Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma","volume":"23","author":"Vilain","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1111\/his.14651","article-title":"Harmonization of programmed death-ligand 1 immunohistochemistry and mRNA expression scoring in metastatic melanoma: A multicentre analysis","volume":"80","author":"Adam","year":"2022","journal-title":"Histopathology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"330","DOI":"10.5858\/arpa.2018-0043-OA","article-title":"Clinical Utility of the Combined Positive Score for Programmed Death Ligand-1 Expression and the Approval of Pembrolizumab for Treatment of Gastric Cancer","volume":"143","author":"Kulangara","year":"2019","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1056\/NEJMoa1504030","article-title":"Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma","volume":"373","author":"Larkin","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3998","DOI":"10.1200\/JCO.22.01599","article-title":"Seven-Year Follow-Up of the Phase III KEYNOTE-006 Study: Pembrolizumab Versus Ipilimumab in Advanced Melanoma","volume":"41","author":"Robert","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"236","DOI":"10.1016\/j.ejca.2018.06.034","article-title":"Outcomes by line of therapy and programmed death ligand 1 expression in patients with advanced melanoma treated with pembrolizumab or ipilimumab in KEYNOTE-006: A randomised clinical trial","volume":"101","author":"Carlino","year":"2018","journal-title":"Eur. J. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1158\/1541-7786.MCR-18-0173","article-title":"A Leukocyte Infiltration Score Defined by a Gene Signature Predicts Melanoma Patient Prognosis","volume":"17","author":"Zhao","year":"2019","journal-title":"Mol. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cell.2016.02.065","article-title":"Genomic and Transcriptomic Features of Response to Anti-PD-1 Therapy in Metastatic Melanoma","volume":"165","author":"Hugo","year":"2016","journal-title":"Cell"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1271","DOI":"10.1016\/j.cell.2015.07.061","article-title":"Non-genomic and Immune Evolution of Melanoma Acquiring MAPKi Resistance","volume":"162","author":"Hugo","year":"2015","journal-title":"Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1172\/JCI91190","article-title":"IFN-\u03b3-related mRNA profile predicts clinical response to PD-1 blockade","volume":"127","author":"Ayers","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"781","DOI":"10.1038\/s41591-020-0818-3","article-title":"Multimodel preclinical platform predicts clinical response of melanoma to immunotherapy","volume":"26","author":"Yang","year":"2020","journal-title":"Nat. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.ccell.2021.11.012","article-title":"Multiomic profiling of checkpoint inhibitor-treated melanoma: Identifying predictors of response and resistance, and markers of biological discordance","volume":"40","author":"Newell","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e143","DOI":"10.1016\/S1470-2045(17)30074-8","article-title":"iRECIST: Guidelines for response criteria for use in trials testing immunotherapeutics","volume":"18","author":"Seymour","year":"2017","journal-title":"Lancet Oncol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1861","DOI":"10.1093\/annonc\/mdy226","article-title":"Pathological assessment of resection specimens after neoadjuvant therapy for metastatic melanoma","volume":"29","author":"Tetzlaff","year":"2018","journal-title":"Ann. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"e1306","DOI":"10.1097\/SLA.0000000000005459","article-title":"Multicenter Experience with Neoadjuvant Therapy in Melanoma Highlights Heterogeneity in Contemporary Practice","volume":"277","author":"Rhodin","year":"2023","journal-title":"Ann. Surg."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1056\/NEJMoa2402604","article-title":"Neoadjuvant Nivolumab and Ipilimumab in Resectable Stage III Melanoma","volume":"391","author":"Blank","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.annonc.2021.03.006","article-title":"Pathological response and tumour bed histopathological features correlate with survival following neoadjuvant immunotherapy in stage III melanoma","volume":"32","author":"Rawson","year":"2021","journal-title":"Ann. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"4987","DOI":"10.1158\/1078-0432.CCR-23-3775","article-title":"Tumor-Infiltrating Lymphocytes in Necrotic Tumors after Melanoma Neoadjuvant Anti-PD-1 Therapy Correlate with Pathologic Response and Recurrence-Free Survival","volume":"30","author":"Ma","year":"2024","journal-title":"Clin. Cancer Res."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Tarhini, A.A., Edington, H., Butterfield, L.H., Lin, Y., Shuai, Y., Tawbi, H., Sander, C., Yin, Y., Holtzman, M., and Johnson, J. (2014). Immune monitoring of the circulation and the tumor microenvironment in patients with regionally advanced melanoma receiving neoadjuvant ipilimumab. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0087705"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1038\/s41591-019-0357-y","article-title":"A single dose of neoadjuvant PD-1 blockade predicts clinical outcomes in resectable melanoma","volume":"25","author":"Huang","year":"2019","journal-title":"Nat. Med."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1327","DOI":"10.1158\/1078-0432.CCR-19-2931","article-title":"Compartmental Analysis of T-cell Clonal Dynamics as a Function of Pathologic Response to Neoadjuvant PD-1 Blockade in Resectable Non-Small Cell Lung Cancer","volume":"26","author":"Zhang","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1038\/s41586-020-2056-8","article-title":"Peripheral T cell expansion predicts tumour infiltration and clinical response","volume":"579","author":"Wu","year":"2020","journal-title":"Nature"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1038\/s41586-019-1922-8","article-title":"B cells and tertiary lymphoid structures promote immunotherapy response","volume":"577","author":"Helmink","year":"2020","journal-title":"Nature"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1649","DOI":"10.1038\/s41591-018-0197-1","article-title":"Neoadjuvant immune checkpoint blockade in high-risk resectable melanoma","volume":"24","author":"Amaria","year":"2018","journal-title":"Nat. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2427\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T16:49:18Z","timestamp":1760028558000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/26\/6\/2427"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,8]]},"references-count":58,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,3]]}},"alternative-id":["ijms26062427"],"URL":"https:\/\/doi.org\/10.3390\/ijms26062427","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,8]]}}}