头颈部鳞状细胞癌免疫治疗的研究进展

doi:10.13591/j.cnki.kqyx.2026.09.012

摘要/Abstract

摘要：

头颈部鳞状细胞癌(head and neck squamous cell carcinoma,HNSCC)的治疗模式在免疫检查点抑制剂(immune checkpoint inhibitors,ICIs)出现后发生了根本性的改变。本文对HNSCC免疫治疗的最新进展进行了系统综述。其中,以程序性死亡受体1(programmed death-1,PD-1)抑制剂为代表的ICIs不仅显著延长了复发/转移性HNSCC患者的总生存期,将其应用拓展至局部晚期疾病的围手术期治疗,也有效提升了患者的病理缓解率与生存率。联合策略(如联合化疗、放疗或靶向治疗)通过协同增效进一步改善了疗效;同时,双特异性抗体、抗体-药物偶联物等新型药物也为治疗提供了更多选择。然而,HNSCC免疫治疗仍面临疗效异质性、耐药机制复杂及现有生物标志物(如PD-L1、肿瘤突变负荷)预测能力不足等挑战。未来研究应聚焦于开发基于多组学的精准分型模型、优化联合策略以克服耐药,并积极探索新型免疫药物。总之,免疫治疗已成为HNSCC综合治疗的基石,其向精准化与多模态方向的持续演进,有望为改善患者预后奠定更坚实的基础。

关键词: 头颈部鳞状细胞癌, 免疫检查点抑制剂, 程序性死亡受体1, 联合治疗, 生物标志物

Abstract:

The treatment paradigm for head and neck squamous cell carcinoma(HNSCC) has undergone fundamental changes since the emergence of immune checkpoint inhibitors(ICIs). This article provides a systematic review of the latest advances in HNSCC immunotherapy. ICIs, represented by PD-1 inhibitors, have not only significantly prolonged the overall survival of patients with recurrent/metastatic HNSCC but have also expanded their application to the perioperative management of locally advanced disease, effectively improving pathological response rates and survival rates. Combination strategies(such as with chemotherapy, radiotherapy, or targeted therapy) have further enhanced efficacy through synergistic effects. Meanwhile, novel agents like bispecific antibodies and antibody-drug conjugates offer additional therapeutic options. However, HNSCC immunotherapy still faces challenges, including heterogeneous responses, complex resistance mechanisms, and the limited predictive power of existing biomarkers(e.g., PD-L1, tumor mutational burden). Future research should focus on developing precision stratification models based on multi-omics, optimizing combination strategies to overcome resistance, and actively exploring novel immunotherapeutic agents. In conclusion, immunotherapy has become a cornerstone of comprehensive HNSCC treatment, and its continuous evolution towards precision and multimodal approaches is expected to lay a more solid foundation for improving patient prognosis.

Key words: head and neck squamous cell carcinoma, immune checkpoint inhibitors, programmed death-1, combination therapy, biomarkers

中图分类号:

R739.8

游腾超, 周蓉, 杨晓红, 胡小华. 头颈部鳞状细胞癌免疫治疗的研究进展[J]. 口腔医学, 2026, 46(9): 713-720.

YOU Tengchao, ZHOU Rong, YANG Xiaohong, HU Xiaohua. Research progress of immunotherapy for head and neck squamous cell carcinoma[J]. Stomatology, 2026, 46(9): 713-720.

参考文献 74

[1]	郑荣寿, 陈茹, 韩冰峰, 等. 2022年中国恶性肿瘤流行情况分析[J]. 中华肿瘤杂志, 2024, 46(3): 221-231.
[2]	Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024[J]. CA Cancer J Clin, 2024, 74(1): 12-49.
[3]	赵卿, 张晓月, 李明. 常见免疫抑制剂在头颈部鳞状细胞癌的应用进展[J]. 临床口腔医学杂志, 2021, 37(2): 121-123.
[4]	蒲莎莎, 胡云峰, 石梅. 局部晚期头颈部鳞状细胞癌新辅助免疫治疗研究进展[J]. 现代肿瘤医学, 2025, 33(2): 303-310.
[5]	Szturz P, Vermorken JB. Immunotherapy in head and neck cancer: Aiming at EXTREME precision[J]. BMC Med, 2017, 15(1): 110. doi: 10.1186/s12916-017-0879-4 pmid: 28571578
[6]	Mehra R, Seiwert TY, Gupta S, et al. Efficacy and safety of pembrolizumab in recurrent/metastatic head and neck squamous cell carcinoma: Pooled analyses after long-term follow-up in KEYNOTE-012[J]. Br J Cancer, 2018, 119(2): 153-159. doi: 10.1038/s41416-018-0131-9
[7]	Aboaid H, Khalid T, Hussain A, et al. Advances and challenges in immunotherapy in head and neck cancer[J]. Front Immunol, 2025, 16: 1596583. doi: 10.3389/fimmu.2025.1596583
[8]	Elghawy O, Barsouk A, Patel R, et al. Impact of immune-related adverse events on survival among patients with head-and-neck squamous cell carcinoma[J]. Immunotherapy, 2024, 16(16/17): 1069-1078. doi: 10.1080/1750743X.2024.2409617
[9]	谢虹, 王俊. 免疫检查点抑制剂相关不良反应的预测和诊断[J]. 中国肿瘤生物治疗杂志, 2025, 32(8): 793-798.
[10]	Burtness B, Harrington KJ, Greil R, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck(KEYNOTE-048): A randomised, open-label, phase 3 study[J]. Lancet, 2019, 394(10212): 1915-1928. doi: S0140-6736(19)32591-7 pmid: 31679945
[11]	Dzienis M, Cundom J, Fuentes CS, et al. Pembrolizumab plus carboplatin and paclitaxel as first-line therapy for recurrent/metastatic head and neck squamous cell carcinoma(KEYNOTE-B10): A single-arm phase Ⅳ trial[J]. J Clin Oncol, 2024, 42(25): 2989-2999. doi: 10.1200/JCO.23.02625 pmid: 39038265
[12]	Haddad RI, Harrington K, Tahara M, et al. Nivolumab plus ipilimumab versus EXTREME regimen as first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck: The final results of CheckMate 651[J]. J Clin Oncol, 2023, 41(12): 2166-2180. doi: 10.1200/JCO.22.00332
[13]	Li XL, Ai L, Liu S, et al. Efficacy and safety of cadonilimab in recurrent/metastatic solid tumors including ICI-treated tumors in clinical practice: Cohorts of head and neck squamous cell carcinoma and cervical cancer[J]. J Clin Oncol, 2025, 43(16_suppl): e17502.
[14]	Hamedi Z, Lo AY, Berkman JD, et al. Comparative analysis of pembrolizumab and cetuximab-based therapy in patients with recurrent/metastatic head and neck squamous cell carcinoma: Real-world data[J]. J Clin Oncol, 2024, 42(16_suppl): 6022.
[15]	Schoenfeld JD, Hanna GJ, Jo VY, et al. Neoadjuvant nivolumab or nivolumab plus ipilimumab in untreated oral cavity squamous cell carcinoma: A phase 2 open-label randomized clinical trial[J]. JAMA Oncol, 2020, 6(10): 1563. doi: 10.1001/jamaoncol.2020.2955
[16]	Liu L, Chen F, Li Y, et al. Neoadjuvant immunotherapy in combination with chemotherapy in resectable locally advanced head and neck squamous cell carcinoma: A randomized, open label, phase Ⅱ clinical trial[J]. J Clin Oncol, 2025, 43(16_suppl): 6043.
[17]	Wang HL, Wang XD, Li YW, et al. Neoadjuvant PD-1 inhibitor combined with Nab-paclitaxel and cisplatin in resectable locally advanced head and neck squamous cell carcinoma(NCT05522985): A randomized, controlled, open label, phase Ⅱ clinical trial[J]. J Clin Oncol, 2025, 43(16_suppl): 6018.
[18]	Cao F, Wu D, Xu PF, et al. An open-label, single-center phase Ⅱ trial of cadonilimab(an anti-PD-1/CTLA-4 bispecific antibody)in combination with platinum-based dual-drug neoadjuvant chemotherapy for locally advanced, resectable head and neck squamous cell carcinoma[J]. J Clin Oncol, 2024, 42(16_suppl): 6044.
[19]	Helou V, Cai WL, Carlson KM, et al. Survival for head and neck squamous cell carcinoma treated with versus without neoadjuvant systemic therapy: A national propensity score-matched analysis[J]. J Clin Oncol, 2025, 43(16_suppl): 6035.
[20]	Wise-Draper TM, Gulati S, Palackdharry S, et al. Phase Ⅱ clinical trial of neoadjuvant and adjuvant pembrolizumab in resectable local-regionally advanced head and neck squamous cell carcinoma[J]. Clin Cancer Res, 2022, 28(7): 1345-1352. doi: 10.1158/1078-0432.CCR-21-3351
[21]	Haddad RI, Ruscica D, Visa A, et al. eVOLVE-HNSCC: A global phase 3 study of volrustomig as sequential therapy for unresected locally advanced head and neck squamous cell carcinoma(LA-HNSCC)following definitive concurrent chemoradiotherapy(cCRT)[J]. J Clin Oncol, 2024, 42(16_suppl): TPS6120.
[22]	Wei J, Montalvo-Ortiz W, Yu L, et al. Sequence of αPD-1 relative to local tumor irradiation determines the induction of abscopal antitumor immune responses[J]. Sci Immunol, 2021, 6(58): eabg0117.
[23]	Liu Y, Dong YP, Kong L, et al. Abscopal effect of radiotherapy combined with immune checkpoint inhibitors[J]. J Hematol Oncol, 2018, 11(1): 104. doi: 10.1186/s13045-018-0647-8
[24]	Zhang ZF, Liu X, Chen DW, et al. Radiotherapy combined with immunotherapy: The dawn of cancer treatment[J]. Signal Transduct Target Ther, 2022, 7: 258.
[25]	Saba NF, Wong SJ, Nasti T, et al. Intensity-modulated reirradiation therapy with nivolumab in recurrent or second primary head and neck squamous cell carcinoma: A nonrandomized controlled trial[J]. JAMA Oncol, 2024, 10(7): 896. doi: 10.1001/jamaoncol.2024.1143 pmid: 38780927
[26]	Roof L, Buchberger D, Yalamanchali A, et al. Patterns and outcomes of palliative radiation therapy with immunotherapy in locally recurrent head and neck squamous cell carcinoma[J]. J Clin Oncol, 2023, 41(16_suppl): e18015.
[27]	Patel R, Elghawy O, Barsouk A, et al. Impact of immune-related adverse events(IrAE)onset on disease response and survival in patients(pts)with head-neck cancer treated with immune check point inhibitors(ICI)[J]. J Clin Oncol, 2024, 42(16_suppl): 6028.
[28]	中国临床肿瘤学会指南工作委员会. 中国临床肿瘤学会(CSCO)免疫检查点抑制剂相关的毒性管理指南[M]. 北京: 人民卫生出版社, 2023.
[29]	Bhatia A, Burtness B. Treating head and neck cancer in the age of immunotherapy: A 2023 update[J]. Drugs, 2023, 83(3): 217-248. doi: 10.1007/s40265-023-01835-2 pmid: 36645621
[30]	Barjij I, Meliani M. Immunogenic cell death as a target for combination therapies in solid tumors: A systematic review toward a new paradigm in immuno-oncology[J]. Cureus, 2025, 17(6): e85776.
[31]	Ali Zeeshan HM, Lee GH, Kim HR, et al. Endoplasmic reticulum stress and associated ROS[J]. Int J Mol Sci, 2016, 17(3): 327. doi: 10.3390/ijms17030327 pmid: 26950115
[32]	Lv JX, Cai JY, Yuan K, et al. Immunogenic cell death inducers: Current advances and future perspectives[J]. Coord Chem Rev, 2025, 542: 216846. doi: 10.1016/j.ccr.2025.216846
[33]	Matsushita M, Moriwaki M. Autophagy modulates immunogenic cell death in cancer[J]. Cancers, 2026, 18(2): 205. doi: 10.3390/cancers18020205
[34]	Fahey CG, Cordova AF, Gedeon PC, et al. Targeting STING to generate therapeutic anti-tumor immunity[J]. Cancer Cell, 2026, 44(2): 260-280. doi: 10.1016/j.ccell.2025.12.002
[35]	Wang M, Shi ML, Ding YM, et al. High cGAS-STING expression associates with improved efficacy of neoadjuvant chemo-immunotherapy in head and neck squamous cell carcinoma[J]. Front Oncol, 2025, 15: 1584061. doi: 10.3389/fonc.2025.1584061
[36]	He ZJ, Jing XM, Dai XY, et al. The ability of clinically relevant chemotherapeutics to induce immunogenic cell death in squamous cell carcinoma[J]. Front Biosci(Landmark Ed), 2024, 29(4): 158.
[37]	Chen SX, Chen YL, Xu YF, et al. Harnessing tumor cell death mechanisms to reshape the immune microenvironment: A novel approach for head and neck cancer therapy[J]. Int Immunopharmacol, 2026, 171: 116132. doi: 10.1016/j.intimp.2025.116132
[38]	Lind H, Strait A, Hall S, et al. Abstract 6646: Investigating the combination of radiation and subsequent immune checkpoint inhibitor treatment in head and neck squamous cell carcinoma models[J]. Cancer Res, 2024, 84(6_Supplement): 6646.
[39]	Rosenberg AJ, Kato S, Johnson D, et al. Abstract 5181: Early activity and biomarker evaluation of NT219 in combination with cetuximab in a Phase 1/2 study of recurrent/metastatic squamous cell carcinoma of the head and neck(R/M SCCHN)[J]. Cancer Res, 2024, 84(6_Supplement): 5181.
[40]	Ju HY, Hu JZ, Wu YT, et al. Cetuximab plus dalpiciclib in patients with HPV-negative, anti-PD-1-resistant recurrent or metastatic head and neck squamous cell carcinoma[J]. J Clin Oncol, 2025, 43(16_suppl): 6026.
[41]	Harrington KJ, Kim HR, Salas S, et al. Abstract PO-003: Lenvatinib with or without pembrolizumab versus chemotherapy for treatment of recurrent or metastatic head and neck squamous cell carcinoma that progressed on platinum therapy and immunotherapy: Phase 2 LEAP-009[J]. Clin Cancer Res, 2023, 29(18_Supplement): PO-3-PO-003.
[42]	Colevas AD, Park JJ, Fang B, et al. A phase 2 study of magrolimab combination therapy in patients with recurrent or metastatic head and neck squamous-cell carcinoma[J]. Int J Radiat Oncol, 2022, 112(5): e42-e43.
[43]	Johnson FM, O’Hara MP, Yapindi L, et al. Phase I/Ⅱ study of the aurora kinase a inhibitor alisertib and pembrolizumab in refractory, Rb-deficient head and neck squamous cell carcinomas[J]. Clin Cancer Res, 2025, 31(3): 479-490. doi: 10.1158/1078-0432.CCR-24-2290 pmid: 39589337
[44]	Qin TT, Mattox AK, Campbell JS, et al. Epigenetic therapy sensitizes anti-PD-1 refractory head and neck cancers to immunotherapy rechallenge[J]. J Clin Investig, 2025, 135(6): e181671. doi: 10.1172/JCI181671
[45]	Sun L, Fayette J, Salas S, et al. Tisotumab vedotin in head and neck squamous cell carcinoma: Updated analysis from innovaTV 207 Part C[J]. J Clin Oncol, 2024, 42(16_suppl): 6012.
[46]	Dong H, Li ML, Yang C, et al. Combination therapy with oncolytic viruses and immune checkpoint inhibitors in head and neck squamous cell carcinomas: An approach of complementary advantages[J]. Cancer Cell Int, 2023, 23(1): 1. doi: 10.1186/s12935-022-02846-x pmid: 36604694
[47]	Vallianou NG, Evangelopoulos A, Kounatidis D, et al. Immunotherapy in head and neck cancer: Where do we stand?[J]. Curr Oncol Rep, 2023, 25(8): 897-912. doi: 10.1007/s11912-023-01425-1 pmid: 37213060
[48]	Harrington KJ, Cohen E, Zandberg DP, et al. A phase 2, open-label, multicenter study investigating efficacy and safety of RP3 oncolytic immunotherapy combined with other therapies in patients with locoregionally advanced or recurrent squamous cell carcinoma of the head and neck[J]. J Clin Oncol, 2023, 41(16_suppl): TPS6106.
[49]	Massarelli E, William W, Johnson F, et al. Combining immune checkpoint blockade and tumor-specific vaccine for patients with incurable human papillomavirus 16-related cancer: A phase 2 clinical trial[J]. JAMA Oncol, 2019, 5(1): 67. doi: 10.1001/jamaoncol.2018.4051 pmid: 30267032
[50]	Cognetti DM, Curry JM, Civantos FF, et al. Recent safety and efficacy findings from a phase 1b/2 open-label combination study of ASP-1929 photoimmunotherapy with anti-PD-1 therapy in EGFR-expressing advanced head and neck squamous cell carcinoma(HNSCC)[J]. J Clin Oncol, 2024, 42(16_suppl): 6083.
[51]	Mei Z, Huang JW, Qiao B, et al. Immune checkpoint pathways in immunotherapy for head and neck squamous cell carcinoma[J]. Int J Oral Sci, 2020, 12(1): 16. doi: 10.1038/s41368-020-0084-8
[52]	姜鑫, 杜国强, 李志勇, 等. OX40免疫检查点在头颈部鳞状细胞癌中的作用机制及临床应用的研究进展[J]. 中国医科大学学报, 2020, 49(6): 570-573.
[53]	Sadeghirad H, Liu N, Monkman J, et al. Compartmentalized spatial profiling of the tumor microenvironment in head and neck squamous cell carcinoma identifies immune checkpoint molecules and tumor necrosis factor receptor superfamily members as biomarkers of response to immunotherapy[J]. Front Immunol, 2023, 14: 1135489. doi: 10.3389/fimmu.2023.1135489
[54]	金凯强, 成立新. B7同源物3在头颈部鳞状细胞癌中的研究进展[J]. 中国现代医生, 2024, 62(6): 140-143.
[55]	Oliva M, Spreafico A, Taberna M, et al. Immune biomarkers of response to immune-checkpoint inhibitors in head and neck squamous cell carcinoma[J]. Ann Oncol, 2019, 30(1): 57-67. doi: S0923-7534(19)31004-X pmid: 30462163
[56]	Ascione A, Botticelli A, Leopizzi M, et al. Immunotherapy in recurrent/metastatic head and neck squamous cell carcinoma: PD-L1 and beyond[J]. Pathologica, 2025, 117(2): 73-83. doi: 10.32074/1591-951X-1092 pmid: 40474706
[57]	黄鹤, 鞠侯雨, 杨文艺, 等. PD-L2在头颈部鳞状细胞癌免疫治疗预后评估中的意义[J]. 中国癌症杂志, 2023, 33(6): 613-618. doi: 10.19401/j.cnki.1007-3639.2023.06.009
[58]	Mandal R, Şenbabaoğlu Y, Desrichard A, et al. The head and neck cancer immune landscape and its immunotherapeutic implications[J]. JCI Insight, 2016, 1(17): e89829. doi: 10.1172/jci.insight.89829
[59]	Zhao M, Schoenfeld JD, Egloff AM, et al. T cell dynamics with neoadjuvant immunotherapy in head and neck cancer[J]. Nat Rev Clin Oncol, 2025, 22(2): 83-94. doi: 10.1038/s41571-024-00969-w pmid: 39658611
[60]	Oliveira G, Egloff AM, Afeyan AB, et al. Preexisting tumor-resident T cells with cytotoxic potential associate with response to neoadjuvant anti-PD-1 in head and neck cancer[J]. Sci Immunol, 2023, 8(87): eadf4968.
[61]	张少秋, 燕丽, 李瑞辰, 等. 头颈部鳞状细胞癌免疫微环境及其作用机制的最新研究进展及展望[J]. 中国癌症杂志, 2023, 33(6): 629-636. doi: 10.19401/j.cnki.1007-3639.2023.06.011
[62]	林树春. Treg、MDSC及PD-1阳性T细胞在头颈部鳞状细胞癌免疫抑制机制的研究[D]. 福州: 福建医科大学, 2019.
[63]	Naei VY, Tubelleza R, Monkman J, et al. Abstract 750: Exploring PD1/PDL1 interactions and macrophage-tumor barriers in head and neck cancer: A spatial approach to immunotherapy response[J]. Cancer Res, 2025, 85(8_Supplement_1): 750. doi: 10.1158/1538-7445.AM2025-750
[64]	Zhang YY, Li JB, Guo XY, et al. Tumor-specific MHC-Ⅱ activates CD4⁺ and CD8⁺ T cells in head and neck squamous cell carcinoma to boost immunotherapy efficacy[J]. Cancer Res, 2025, 85(17): 3258-3274.
[65]	Bettegowda C, Sausen M, Leary R, et al. Detection of circulating tumor DNA in early and late stage human malignancies[J]. Neuro Oncol, 2014, 16(suppl 3): iii7.
[66]	Yin J, Xu L, Wang SG, et al. Integrating immune multi-omics and machine learning to improve prognosis, immune landscape, and sensitivity to first- and second-line treatments for head and neck squamous cell carcinoma[J]. Sci Rep, 2024, 14: 31454. doi: 10.1038/s41598-024-83184-y
[67]	Laliotis G, Ugwu C, Wolden M. The molecular landscape of immunotherapy treatment and advanced disease in head and neck squamous carcinoma(HNSCC)[J]. J Clin Oncol, 2025, 43(16_suppl): 6032.
[68]	张娣, 董梅. 头颈部鳞癌免疫治疗靶点的研究进展[J]. 中华肿瘤防治杂志, 2022, 29(1): 72-78.
[69]	Hu JW, Li Y, Lian BJ, et al. Mechanism and role of regulated cell death in tumor immunity and immunotherapy[J]. Cancer Commun, 2025, 45(11): 1456-1495. doi: 10.1002/cac2.70064
[70]	Li CF, Li YZ, Wang ZJ, et al. Nanomedicine leverages cuproptosis-mediated cGAS-STING activation to enhance antitumor immunity[J]. J Nanobiotechnol, 2026, 24(1): 271. doi: 10.1186/s12951-026-04203-w
[71]	Wan J, Shi JH, Shi M, et al. Lactate dehydrogenase B facilitates disulfidptosis and exhaustion of tumour-infiltrating CD8⁺ T cells[J]. Nat Cell Biol, 2025, 27(6): 972-982. doi: 10.1038/s41556-025-01673-2
[72]	Li MY, Jiang P, Yang YH, et al. The role of pyroptosis and gasdermin family in tumor progression and immune microenvironment[J]. Exp Hematol Oncol, 2023, 12(1): 103. doi: 10.1186/s40164-023-00464-5 pmid: 38066523
[73]	Brambilla M, Zanichelli A, Cancila V, et al. Neutrophil extracellular traps in cancer: Immune modulation, therapy resistance, and the dilemma of targeting[J]. Cell Death Dis, 2025, 16: 882. doi: 10.1038/s41419-025-08218-3
[74]	Zhou J, Yang Y, Fang YN, et al. Targeting cGAS-STING signaling and cell death modes in cancer and autoimmune diseases[J]. Cytokine Growth Factor Rev, 2025, 85: 56-80. doi: 10.1016/j.cytogfr.2025.07.004