Ipilimumab

In 2025, muzastotug showed 29% confirmed overall response rate (ORR) among 21 patients with MSS CRC in the 20 mg/kg dose cohorts Median overall survival (OS) for the 10 mg/kg cohorts was 19.4 months, with a median follow-up of 17.8 months 4% overall discontinuation rate, no dose limiting toxicities, and no Grade 4 or 5 treatment-related adverse events (TRAEs) across 67 patients in all dose cohorts supports improved tolerability pro muzastotug Randomized Phase 2 trial enrollment ahead of plan, with potential updates in 2026 and results expected in 1H 2027; registration trial expected to begin once optimal dose regimen has been established Cash and cash equivalents of $74.5 million as of December 31, 2025, plus proceeds raised from the ATM Offering in 2026 year-to-date, anticipated to provide cash runway into early 2028 SAN DIEGO, Calif. and SUZHOU, China, April 01, 2026 (GLOBE NEWSWIRE) -- Adagene Inc. (“Adagene”) (Nasdaq: ADAG), a platform-driven, clinical-stage biotechnology company transforming the discovery and development of novel anti-body-based therapies, today reported financial results for the full year 2025 and provided corporate updates. “Our clinical data for muzastotug plus pembrolizumab consistently demonstrate potent, dose-dependent efficacy,” said Peter Luo, Ph.D., Chairman and President of R&D at Adagene. “The 10 mg/kg data reported at ASCO have now matured into the classic long survival tail of CTLA-4 inhibition. By significantly mitigating severe toxicities, patients remain on therapy longer, allowing CTLA-4-mediated intratumoral Treg depletion, alongside PD-1-mediated reinvigoration and CTLA-4-mediated priming of effector T cells, to drive durable disease control. Importantly, these data provide a clear, de-risked read-through to the 20 mg/kg dose, which already shows an encouraging 29% ORR with median duration of response not yet reached. “Supported by Fast Track Designation and FDA alignment under Project Optimus, we are on track to finalize the optimal combination dose regimen for a potential MSS colorectal cancer registrational trial. The expanded therapeutic window also helps to establish muzastotug as a foundational combination backbone. At AACR, we will showcase this potential with data from triplet regimens—combining with fruquintinib in 3L+ MSS CRC, alongside results from the Morpheus Liver study evaluating a triplet of muzastotug, atezolizumab, and bevacizumab versus atezolizumab and bevacizumab alone in first-line HCC. These readouts underscore our ability to safely unlock deeper responses in hard-to-treat tumors.” 2026 OBJECTIVES & CASH RUNWAY INTO EARLY 2028 Data update from the ongoing Phase 1b/2 study of muzastotug in combination with Merck’s (known as MSD outside of the United States and Canada) anti-PD-1 therapy, KEYTRUDA ® (pembrolizumab) in 3L+ MSS CRC, including 41 patients in the 10 mg/kg cohorts and 26 patients in the 20 mg/kg cohorts Complete enrollment of the ongoing randomized Phase 2 dose-optimization study with muzastotug, which is being conducted in alignment with FDA Project Optimus, and designed to allow dose regimen selection for Phase 3. Provide preliminary clinical data, including pathological responses, to inform future development from investigator-initiated Phase 2 trial for neoadjuvant muzastotug + pembrolizumab in colorectal cancer. Provide initial clinical data from a new cohort of patients in the ongoing Phase 1b/2 study of muzastotug + pembrolizumab in combination with standard of care (fruquintinib) in MSS CRC patients. Share results of the clinical trial collaboration with Roche, which evaluates muzastotug in triplet combination with atezolizumab and bevacizumab in first-line treatment of locally advanced or metastatic hepatocellular carcinoma (HCC; liver cancer). Establish additional collaboration/licensing agreements. With cash and cash equivalents of $74.5 million as of December 31, 2025, plus proceeds raised from the ATM Offering in 2026 year-to-date, Company expects a cash runway extending into early 2028. PIPELINE HIGHLIGHTS ADG126- Phase 1b/2 data: As presented at ASCO 2025, muzastotug showed 29% (6/21) confirmed overall response rate (ORR) in the combined 20 mg/kg dose cohorts. Among 41 patients in the combined 10mg/kg dose cohorts, median overall survival (mOS) was 19.4 months with a 17.8-month median follow-up, which compares favorably to 11-12 month mOS from fruquintinib Phase 3 trials in the same population 1 Across 67 patients in all cohorts, a low 4% overall discontinuation rate, no dose limiting toxicities, and no Grade 4 or 5 treatment-related adverse events (TRAEs); Grade 3 TRAEs were 15% in the 10 mg/kg cohorts and 27% in the 20 mg/kg cohorts, which were generally transient and manageable. Updated data demonstrate the durability of response and further support the optimized therapeutic index pro muzastotug, which overcomes well-known dose-limiting toxicities of other CTLA-4 inhibitors at 10-20-fold higher doses 2 , to provide potentially improved efficacy. Randomized Phase 2 trial enrollment ongoing, with results expected in 1H 2027; registration trial expected to begin once optimal dose regimen has been established AMERICAN ASSOCIATION FOR CANCER RESEARCH 2026 PRESENTATIONS The following abstracts have been selected for presentation at AACR 2026: 1) Title: Ph1b evaluation of ADG126 (muzastotug, an anti-CTLA-4 masking antibody) pembrolizumab (Pembro) IO doublet in combination with fruquintinib (Fruq) in advanced and metastatic microsatellite stable colorectal cancer This poster will provide initial clinical data from a new cohort of patients in the ongoing Phase 1b/2 study of muzastotug + pembrolizumab in combination with standard of care (fruquintinib) in MSS CRC patients. 2) Title: Results from the phase 1b/2 Morpheus Liver study in patients with unresectable locally advanced or metastatic hepatocellular carcinoma (HCC): Muzastotug (ADG126: masked anti-CTLA-4 Ab) combination arm This poster will share results of the clinical trial collaboration with Roche, which evaluates muzastotug in triplet combination with atezolizumab and bevacizumab in first-line treatment of liver cancer. 3) Title: Preclinical characterization of XB404, a masked anti-ROR1/2 antibody-drug conjugate Partner Exelixis will present preclinical data from antibody-drug conjugate, XB404, built with Adagene’s SAFEbody masking technology and designed to deliver a cytotoxic payload to ROR1/2-expressing tumors while minimizing on-target, off-tumor side effects. ONGOING COLLABORATIONS Sanofi: Invested up to $25 million to support muzastotug’s randomized Phase 2 study. Separately, Adagene will supply Sanofi with muzastotug to evaluate the safety, efficacy, pharmacokinetics and biomarker data in combination with Sanofi’s SAR445877 (PD-1 x IL-15 fusion protein) in over 100 patients in a Phase 1/2 clinical trial in advanced solid tumors. Sanofi also exercised its option for a third SAFEbody® discovery program. Third Arc Bio: Partnered to develop two masked CD3 T cell engagers, expanding SAFEbody® into next-generation T cell therapies. Exelixis: Advanced a third masked ADC against a solid tumor target, building on the 2021 collaboration. ConjugateBio: Collaborated on bispecific ADCs using Adagene-derived antibody, further demonstrating scalable platform potential. Roche: Roche is sponsoring and conducting a phase 1b/2 multi-national trial to evaluate ADG126 in a triple combination with atezolizumab and bevacizumab in first-line hepatocellular carcinoma (HCC). FINANCIAL HIGHLIGHTS Cash and Cash Equivalents: Cash and cash equivalents were US$74.5 million as of December 31, 2025, compared to US$85.2 million as of December 31, 2024. Total borrowings from commercial banks in China (denominated in RMB) decreased to US$6.1 million as of December 31, 2025 from US$18.2 million as of December 31, 2024. The associated loan proceeds were primarily used to pay for the company’s R&D activities in China. Net Revenue: Net revenue was US$7.7 million for the year ended December 31, 2025, compared to US$0.1 million in 2024. The increase of approximately 7,333% reflects net revenue recognized upon fulfillment of certain performance obligations associated with the collaboration and technology licensing agreements with Sanofi, ConjugateBio and Third Arc Bio, respectively. Research and Development (R&D) Expenses: R&D expenses were US$22.0 million for the year ended December 31, 2025, compared to US$28.8 million in 2024. The decrease of approximately 23% in R&D expenses reflects clinical focus on and prioritization of the company’s masked, anti-CTLA-4 SAFEbody ADG126. Administrative Expenses: Administrative expenses were US$7.1 million for the year ended December 31, 2025, compared to US$7.3 million in 2024. The decrease was mainly a result of cost-control measures. Net Loss: Net loss attributable to Adagene Inc.’s shareholders was US$17.6 million for the year ended December 31, 2025, compared to US$33.4 million in 2024. Ordinary Shares Outstanding: As of December 31, 2025, there were 59,231,993 ordinary shares issued and outstanding. Each American depository share, or ADS, represents one and one quarter (1.25) ordinary shares of the company. Non-GAAP Net Loss: Non-GAAP net loss, which is defined as net loss attributable to ordinary shareholders for the period after excluding share-based compensation expenses, was US$13.9 million for the year ended December 31, 2025, compared to US$28.5 million in 2024. Please refer to the section in this press release titled “Reconciliation of GAAP and Non-GAAP Results” for details. Non-GAAP Financial Measures: The company uses non-GAAP net loss and non-GAAP net loss per ordinary shares for the year, which are non-GAAP financial measures, in evaluating its operating results and for financial and operational decision-making purposes. The company believes that non-GAAP net loss and non-GAAP net loss per ordinary shares for the year help identify underlying trends in the company’s business that could otherwise be distorted by the effect of certain expenses that the company includes in its loss for the year. The company believes that non-GAAP net loss and non-GAAP net loss per ordinary shares for the year provide useful information about its results of operations, enhances the overall understanding of its past performance and future prospects and allows for greater visibility with respect to key metrics used by its management in its financial and operational decision-making. Non-GAAP net loss and non-GAAP net loss per ordinary shares for the year should not be considered in isolation or construed as an alternative to operating profit, loss for the year or any other measure of performance or as an indicator of its operating performance. Investors are encouraged to review non-GAAP net loss and non-GAAP net loss per ordinary shares for the year and the reconciliation to their most directly comparable GAAP measures. Non-GAAP net loss and non-GAAP net loss per ordinary shares for the year here may not be comparable to similarly titled measures presented by other companies. Other companies may calculate similarly titled measures differently, limiting their usefulness as comparative measures to the company’s data. The company encourages investors and others to review its financial information in its entirety and not rely on a single financial measure. Non-GAAP net loss and non-GAAP net loss per ordinary shares for the year represent net loss attributable to ordinary shareholders for the year excluding share-based compensation expenses. Share-based compensation expense is a non-cash expense arising from the grant of stock-based awards to employees. The company believes that the exclusion of share-based compensation expenses from the net loss in the Reconciliation of GAAP and Non-GAAP Results assists management and investors in making meaningful period-to-period comparisons in the company's operating performance or peer group comparisons because (i) the amount of share-based compensation expenses in any specific period may not directly correlate to the company’s underlying performance, (ii) such expenses can vary significantly between periods as a result of the timing of grants of new stock-based awards, and (iii) other companies may use different forms of employee compensation or different valuation methodologies for their share-based compensation. Please see the “Reconciliation of GAAP and Non-GAAP Results” included in this press release for a full reconciliation of non-GAAP net loss and non-GAAP net loss per ordinary shares for the year to net loss attributable to ordinary shareholders for the year/period. 1 Qin S, Xu RH, Shen L, Et Al. Subgroup Analysis By Liver Metastasis In The FRESCO Trial Comparing Fruquintinib Versus Placebo Plus Best Supportive Care In Chinese Patients With Metastatic Colorectal Cancer. Onco Targets Ther. 2021;14:4439-; Garcia-Carbonero R, Dasari NA, Eng C, et al. 520P Efficacy and safety of fruquintinib in patients with refractory metastatic colorectal cancer with and without liver metastasis: A subgroup analysis of the phase III FRESCO-2 trial. Ann Onc 2024;35:S439 2 (i) CheckMate 511 (Phase IIIb/IV): This study compared nivolumab 3 mg/kg plus ipilimumab 1 mg/kg Q3W × 4 versus the standard nivolumab 1 mg/kg plus ipilimumab 3 mg/kg Q3W × 4 in patients with advanced melanoma. The trial demonstrated similar efficacy with a significantly lower incidence of Grade 3–5 treatment-related adverse events (34% vs. 48%); and (ii) Lebbé C, et al. (2019). Evaluation of two dosing regimens for nivolumab in combination with ipilimumab in patients with advanced melanoma: Results from the Phase IIIb/IV CheckMate 511 trial. Journal of Clinical Oncology, 37(11):867–875. About Adagene Adagene Inc. (Nasdaq: ADAG) is a platform-driven, clinical-stage biotechnology company committed to transforming the discovery and development of novel antibody-based cancer immunotherapies. Adagene combines computational biology and artificial intelligence to design novel antibodies that address globally unmet patient needs. The company has forged strategic collaborations with reputable global partners that leverage its SAFEbody precision masking technology in multiple approaches at the vanguard of science. Powered by its proprietary Dynamic Precision Library (DPL) platform, composed of NEObody™, SAFEbody, and POWERbody™ technologies, Adagene’s highly differentiated pipeline features novel immunotherapy programs. The company’s SAFEbody technology is designed to address safety and tolerability challenges associated with many antibody therapeutics by using precision masking technology to shield the binding domain of the biologic therapy. Through activation in the tumor microenvironment, this allows for tumor-specific targeting of antibodies, while minimizing on-target off-tumor toxicity in healthy tissues. Adagene’s lead clinical program, muzastotug (ADG126), is a masked, anti-CTLA-4 SAFEbody with FDA Fast Track designation that targets a unique epitope of CTLA-4 in regulatory T cells (Tregs) in the tumor microenvironment. Muzastotug is currently in Phase 1b/2 and Phase 2 clinical studies in combination with anti-PD-1 therapy, particularly focused on microsatellite stable (MSS) metastatic colorectal cancer (CRC). Validated by ongoing clinical research, the SAFEbody platform can be applied to a wide variety of antibody-based therapeutic modalities, including Fc empowered antibodies, antibody-drug conjugates, and bi/multi-specific T-cell engagers. For more information, please visit: Follow Adagene on WeChat, LinkedIn and X. SAFEbody® is a registered trademark in the United States, China, Australia, Japan, Singapore, and the European Union. KEYTRUDA® is a registered trademark of Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA.. Safe Harbor Statement This press release contains forward-looking statements, including statements regarding certain clinical results of ADG126, the potential implications of clinical data for patients, and Adagene’s advancement of, and anticipated preclinical activities, clinical development, regulatory milestones, and commercialization of its product candidates. Actual results may differ materially from those indicated in the forward-looking statements as a result of various important factors, including but not limited to Adagene’s ability to demonstrate the safety and efficacy of its drug candidates; the clinical results for its drug candidates, which may not support further development or regulatory approval; the content and timing of decisions made by the relevant regulatory authorities regarding regulatory approval of Adagene’s drug candidates; Adagene’s ability to achieve commercial success for its drug candidates, if approved; Adagene’s ability to obtain and maintain protection of intellectual property for its technology and drugs; Adagene’s reliance on third parties to conduct drug development, manufacturing and other services; Adagene’s limited operating history and Adagene’s ability to obtain additional funding for operations and to complete the development and commercialization of its drug candidates; Adagene’s ability to enter into additional collaboration agreements beyond its existing strategic partnerships or collaborations, and the impact of the COVID-19 pandemic on Adagene’s clinical development, commercial and other operations, as well as those risks more fully discussed in the “Risk Factors” section in Adagene’s filings with the U.S. Securities and Exchange Commission. All forward-looking statements are based on information currently available to Adagene, and Adagene undertakes no obligation to publicly update or revise any forward-looking statements, whether as a result of new information, future events or otherwise, except as may be required by law. Investor Contacts: Raymond Tam Raymond_tam@adagene.com Corey Davis LifeSci Advisors cdavis@lifesciadvisors.com Media: Lindsay Rocco Elixir Health Public Relations 1-862-596-1304 lrocco@elixirhealthpr.com Unaudited Consolidated Balance Sheets December 31, 2024 December 31, 2025 US$ US$ ASSETS Current assets: Cash and cash equivalents 85,194,502 74,523,782 Amounts due from related parties 8,309 17,349 Prepayments and other current assets 2,575,194 2,834,034 Total current assets 87,778,005 77,375,165 Property, equipment and software, net 1,125,389 717,374 Operating lease right-of-use assets 283,645 145,535 Other non-current assets 81,386 25,223 TOTAL ASSETS 89,268,425 78,263,297 LIABILITIES AND SHAREHOLDERS’ EQUITY Current liabilities: Accounts payable 4,241,773 2,884,507 Contract liabilities — 3,462,683 Amounts due to related parties 13,187,966 10,347,200 Accruals and other current liabilities 2,816,038 2,790,794 Income tax payable 5,265 410,198 Warrant liabilities — 205,146 Short-term borrowings 4,868,956 4,268,154 Current portion of long-term borrowings 12,923,599 711,359 Current portion of operating lease liabilities 141,341 92,055 Total current liabilities 38,184,938 25,172,096 Long-term borrowings 417,339 1,138,174 Operating lease liabilities 142,304 53,480 TOTAL LIABILITIES 38,744,581 26,363,750 Commitments and contingencies Mezzanine equity: Series A non-voting contingently redeemable convertible preferred shares (par value of US$0.0001 per share; nil authorized, issued and outstanding as of December 31, 2024; and 1,062,500 shares authorized, issued and outstanding as of December 31, 2025) — 16,550,000 Total mezzanine equity — 16,550,000 Shareholders’ equity: Ordinary shares (par value of US$0.0001 per share; 640,000,000 shares authorized, and 58,886,944 shares issued and outstanding as of December 31, 2024; and 640,000,000 shares authorized, and 59,231,993 shares issued and outstanding as of December 31, 2025) 5,889 5,923 Additional paid-in capital 362,220,445 366,043,455 Accumulated other comprehensive loss (526,903 ) (1,914,831 ) Accumulated deficit (311,175,587 ) (328,785,000 ) Total shareholders’ equity 50,523,844 35,349,547 TOTAL LIABILITIES, MEZZANINE EQUITY AND SHAREHOLDERS’ EQUITY 89,268,425 78,263,297 Unaudited Consolidated Statements of Comprehensive Loss For the Year Ended December 31, 2024 For the Year Ended December 31, 2025 US$ US$ Revenues Licensing and collaboration revenue 103,204 7,670,902 Operating expenses and income Research and development expenses (28,781,412 ) (22,033,573 ) Including external related parties (1,943,523 ) (1,580,387 ) Administrative expenses (7,273,335 ) (7,075,624 ) Loss from operations (35,951,543 ) (21,438,295 ) Interest and investment income 3,801,345 2,303,990 Interest expense (851,874 ) (463,132 ) Other income, net 466,620 323,988 Foreign exchange gain (loss), net (906,212 ) 1,318,235 Change in fair value of warrant liabilities — 47,941 Loss before income tax (33,441,664 ) (17,907,273 ) Income tax benefit 17,553 297,860 Net loss attributable to Adagene Inc.’s shareholders (33,424,111 ) (17,609,413 ) Other comprehensive income (loss) Foreign currency translation adjustments, net of nil tax 1,273,185 (1,387,928 ) Total comprehensive loss attributable to Adagene Inc.’s shareholders (32,150,926 ) (18,997,341 ) Net loss attributable to Adagene Inc.’s shareholders (33,424,111 ) (17,609,413 ) Net loss attributable to ordinary shareholders (33,424,111 ) (17,609,413 ) Weighted average number of ordinary shares used in per share calculation: —Basic 56,287,903 59,006,129 —Diluted 56,287,903 59,006,129 Net loss per ordinary share —Basic (0.59 ) (0.30 ) —Diluted (0.59 ) (0.30 ) Reconciliation of GAAP and Non-GAAP Results For the Year Ended December 31, 2024 For the Year Ended December 31, 2025 US$ US$ GAAP net loss attributable to ordinary shareholders (33,424,111 ) (17,609,413 ) Add back: Share-based compensation expenses 4,909,573 3,741,548 Non-GAAP net loss (28,514,538 ) (13,867,865 ) Weighted average number of ordinary shares used in per share calculation: —Basic 56,287,903 59,006,129 —Diluted 56,287,903 59,006,129 Non-GAAP net loss per ordinary share —Basic (0.51 ) (0.24 ) —Diluted (0.51 ) (0.24 )

引言：超过三十年的生存困局与免疫破冰 在肺癌的浩瀚星图中，小细胞肺癌（SCLC）始终是一颗令人不安的暗星。它以极高的侵袭性、极快的倍增时间和极易发生早期转移的特点，成为名副其实的“顽疾”。在过去长达三十年的时间里，含铂双药化疗几乎是唯一的救命稻草，但患者的 5 年生存率始终在 7% 以下徘徊，无数靶向与新药研发在此折戟沉沙。 直到免疫检查点抑制剂（ICIs）的横空出世，这潭死水才终于泛起涟漪。从单药探索到“免疫+化疗”的联合基石，广泛期小细胞肺癌（ES-SCLC）的中位总生存期（mOS）终于历史性地跨越了 1 年的门槛，最新联合方案甚至将其推向了将近 20 个月的新高度。然而，大多数患者最终仍难逃耐药复发的宿命。 在这场与“最恶肺癌”的博弈中，我们究竟走到了哪一步？下一步的突破口又在哪里？2026 年，《Cancer Letters》期刊发表了由中国医科大学附属第一医院赵明芳教授等人团队领衔的重磅综述《广泛期小细胞肺癌的免疫治疗：现状、挑战与未来策略》。本期推文将以这篇极具穿透力的“战报”为线索，全面复盘 ES-SCLC 的免疫治疗演进史，深度剖析耐药机制，并前瞻性地指出未来的破局之道。十年磨一剑：ES-SCLC 免疫治疗的“狂飙”之路 要理解当前的治疗格局，必须先回望来时路。综述中极其精辟地将 ES-SCLC 免疫治疗的发展史划分为三个关键阶段。 Fig. 1：ES-SCLC 免疫治疗里程碑时间轴 图中清晰展示了免疫治疗在 ES-SCLC 领域的三个发展阶段。从 2016-2017 年的单药探索碰壁，到 2018-2019 年 PD-L1 联合化疗奠定一线基石，再到 2020-2025 年 PD-1 阵营的全面爆发及四药联合方案的突破，生存期天花板被不断击穿。 探索期（2016-2017）：屡败屡战的黑夜 早期的探索步履维艰。2016 年，伊匹木单抗（Ipilimumab）联合化疗的 III 期 CA184-156 研究宣告失败，并未带来 OS 获益。随后帕博利珠单抗在 KEYNOTE-028 试验中展现了单药后线的微弱曙光，但距离改变标准治疗仍有距离。 奠基期（2018-2019）：PD-L1 破冰，确立一线标准 2018 年是 SCLC 历史上的转折点。IMpower133 试验首次证实，阿替利珠单抗联合化疗能将 mOS 提升至 12.3 个月，打破了 20 年的生存僵局。紧接着 2019 年的 CASPIAN 研究再次证实了度伐利尤单抗联合化疗的卓越疗效（mOS 12.9 个月）。PD-L1 抑制剂正式成为 ES-SCLC 的一线基石。 扩张期（2020-2025）：群雄逐鹿，四药联合刷新纪录 进入 2020 年代，PD-1 抑制剂开始强力入局。从国药之光阿得贝利单抗（CAPSTONE-1，mOS 15.3 个月）到斯鲁利单抗（ASTRUM-005，mOS 15.4 个月），再到 2024-2025 年间替雷利珠单抗（Rationale-312）和特瑞普利单抗（EXTENTORCH）的相继获批，免疫联合化疗呈现出百花齐放的态势。最具颠覆性的是 2024 年公布的 ETER701 试验：本维利单抗+安罗替尼+化疗的“四药联合”方案，史无前例地将 mOS 拔高至 19.3 个月，彻底终结了“小细胞肺癌活不过一年半”的魔咒。核心临床试验数据全景对比 机制深扒：为什么大多数患者仍难逃“耐药”宿命？ 尽管前线的战绩极其辉煌，但临床医生最痛心的，依然是患者在几个月后的复发。要理解 SCLC 免疫治疗的艰难，必须看透其狡猾的“反侦察”生存哲学。如果把人体的免疫系统比作一支军队，那么 SCLC 的肿瘤微环境（TME）就是一个冰冷且戒备森严的“极地堡垒”。 [ Fig. 2：小细胞肺癌免疫耐药机制图] 全面揭示了 SCLC 免疫耐药的核心机制：A. 免疫“冷”微环境与多重检查点（CTLA-4/TIM-3等）的代偿上调；B. 肿瘤异质性与治疗压力下的表型转换；C. MHC-I 降解导致抗原递呈失败；D. 巨噬细胞串扰与 PI3K/AKT 通路异常。 “隐身衣”策略：MHC-I 表达下调相比非小细胞肺癌，SCLC 细胞表面的主要组织相容性复合体 I 类（MHC-I）表达极低。这就好比敌军脱下了制服，让巡逻的 CD8+ T 细胞彻底变成了“盲人”，无法识别并杀伤肿瘤细胞。 多重“烟雾弹”：免疫检查点代偿与 T 细胞耗竭即便少部分 T 细胞成功潜入肿瘤内部，SCLC 也会迅速释放“烟雾弹”。在 PD-L1 被药物封锁后，肿瘤微环境中会代偿性地大量表达 CTLA-4、LAG-3、TIM-3 以及 TIGIT 等其他抑制性受体。T 细胞在这些重重阻碍下，陷入深深的“耗竭（Exhaustion）”状态。 致命的“变色龙”：高度异质性与表型转换SCLC 并非一种均质的疾病，目前学界将其分为四大亚型：SCLC-A、N、P、Y。 神经内分泌高表达（NE-high）的 A 型和 N 型，往往是典型的免疫“冷”肿瘤。 神经内分泌低表达（NE-low）的 P 型和 Y 型，MHC-I 表达更高，属于免疫“热”肿瘤。 最棘手的是，在免疫治疗的“清剿”下，NE-low 亚克隆虽然被消灭，但肿瘤会发生“表型转换（Phenotype switching）”，耐药的 NE-high 克隆迅速扩张，最终导致疾病全面失控复发。破局与颠覆：次世代“魔法子弹”重装上阵 面对化免联合方案带来的“天花板”和狡猾的耐药机制，科学家们正在用全新的武器库重塑 SCLC 的治疗范式。综述中详尽梳理了正处于爆发前夜的前沿疗法： [ Fig. 3：ES-SCLC 新兴治疗策略图] 展示了即将颠覆 SCLC 格局的次世代武器库，包括靶向 DLL3 的 CAR-T 细胞疗法、双特异性抗体（BiTEs、PD-1/VEGF）、抗体偶联药物（ADCs）、放射性核素疗法（RPT）、溶瘤病毒以及 PARP 抑制剂的作用机制。1. T 细胞衔接器与双特异性抗体（BsAb） BiTEs（双特异性 T 细胞衔接器）：Tarlatamab（AMG 757） 堪称近年来的超级明星。它一头精准结合 SCLC 细胞表面高表达的 DLL3 靶点，另一头牢牢抓住 T 细胞上的 CD3，强行让 T 细胞与肿瘤细胞“贴脸输出”。在 DeLLphi-304 Ⅲ期试验中，其超越标准化疗的 OS 获益（13.6 vs 8.3 个月）已使其火速获得 FDA 批准作为二线治疗新选择。 双靶点阻断双抗：依沃西单抗（Ivonescimab） 能够同时阻断 PD-1（解除免疫刹车）与 VEGF（改善肿瘤血管正常化）。在针对 ES-SCLC 的 Ib 期研究中，10 mg/kg 剂量组展现出了高达 90.9% 的惊人客观缓解率（ORR），极具前线突围的潜力。2. 抗体偶联药物（ADCs）：重塑微环境的“特洛伊木马” ADC 药物不仅仅是精准投递毒素的“生物导弹”，其毒素释放引起的“旁观者效应”和免疫原性细胞死亡，能直接把冷肿瘤“烧热”。 DLL3-ADC： 在前期 Rova-T 遗憾折戟后，新一代 ADC 如 ZL-1310 强势接棒。早期试验显示其 ORR 高达 68%，且对脑转移患者也有持久疗效。 多靶点开花： 靶向 TROP2 的 戈沙妥珠单抗（SG）（二线 ORR 41.9%）、靶向 B7-H3 的 HS-20093（ORR 63.6%）及 I-DXd（脑转移 ORR 达 37.8%），正在为免疫耐药后的患者构建起坚固的“护城河”。3. 放疗（RT）与核素靶向治疗（RPT）的“破冰”联手 低剂量放疗（LDRT）： 并不是为了直接“烧死”肿瘤，而是为了触发 cGAS-STING 通路激活抗肿瘤免疫。中国学者开展的 MATCH 试验 证实，低剂量胸部放疗联合阿替利珠单抗与化疗，将一线 ORR 拔高至 87.5%。 核素靶向治疗（RPT）： 将放射性核素（如 177Lu 或 α 粒子发射体）与靶向 DLL3 或 CXCR4 的配体结合，犹如在肿瘤内部引爆微型核弹。不仅能实施精准杀伤，还能释放大量肿瘤抗原，与免疫抑制剂产生极强的协同化学反应。临床决策与未来风向：走向“量体裁衣”的个体化时代 基于综述的核心精神，未来 3-5 年内，SCLC 的临床决策将彻底告别“一刀切”。基于分子分型和免疫微环境特征的精准医疗体系即将到来： 初诊评估全面革新： 通过空间转录组学等多组学技术深入解析SCLC的分子亚型（如ASCL1/NEUROD1等），有助于理解肿瘤异质性，并可能为未来实现像非小细胞肺癌那样的靶向分型治疗提供理论基础。 一线及维持治疗的精准分流： 对于高血管生成特征人群，倾向于采用“四药联合”（如 ETER701 模式）。 对于 NE-high (免疫冷肿瘤) 亚型患者，在维持阶段可能更需要联合靶向 DLL3 的药物（如 Tarlatamab、DLL3-ADC）或低剂量放疗进行增敏。 对于 NE-low (免疫热肿瘤) 亚型（如 SCLC-P 型），可能会尝试强化免疫双抗或联合 PARP 抑制剂。 免疫微环境靶向药入局： 能够恢复 MHC-I 表达的 LSD1 抑制剂、特异性激活 CD8+ T 细胞的个体化 mRNA 癌症疫苗，有望在未来与现有免疫基石形成极具杀伤力的联合阵列。Take Away 核心要点总结 里程碑突破： ES-SCLC 的免疫治疗已通过联合化疗与抗血管生成药物，成功将中位总生存期推高至近 20 个月的历史新高，但耐药依然是核心痛点。 耐药深层逻辑： SCLC 的“免疫冷”表型、MHC-I 表达缺失，以及分子亚型间的高异质性与表型转换，是患者复发的根本元凶。 新星闪耀： 靶向 DLL3 的 T 细胞衔接器（Tarlatamab）、多靶点 ADCs（如 ZL-1310、HS-20093）、PD-1/VEGF 双抗以及靶向核素疗法（RPT）代表了目前最具潜力的破局方向。 未来范式： 摒弃“一刀切”，走向基于动态分子分型的个体化精准医疗。 🔥 【同行互动话题】各位同道，在临床实战中，面对一线“免疫+化疗”耐药进展后的 ES-SCLC 患者，您目前更倾向于推荐重启另一种机制的联合免疫（如跨线使用双抗/血管靶向），还是更期待直接上新型 ADC 或 BiTE 药物？欢迎在评论区留下您的犀利观点，我们一起探讨！ 核心文献来源：Yan J-S, Wang Y-Z, Zhao S-Y, et al. Immunotherapy for extensive-stage small cell lung cancer: current status, challenges and future strategies. Cancer Letters 645 (2026) 218382.