Cabozantinib (s)-Malate

作者：汪梓昱 美工：何国红 罗真真 排版：马超 01 引言：肿瘤免疫抗体疗法的崛起 在人类对抗癌症的征途中，治疗手段正经历深刻变革——从传统的手术、放疗和化疗，逐步演进至精准的分子靶向治疗，再到以激活自身免疫力为核心的肿瘤免疫治疗。 2025年诺贝尔生理学或医学奖授予Mary Brunkow、Fred Ramsdell与Shimon Sakaguchi，以表彰他们揭示调节性T细胞（Tregs）在维持“外周免疫耐受”中的关键机制。这一发现奠定了理解免疫系统如何避免攻击自身组织的基础，推动了针对癌症的免疫疗法开发。 这一奖项与2018年诺贝尔生理学或医学奖相呼应，后者授予James P. Allison和Tasuku Honjo，以表彰他们发现通过抑制免疫负调控（如PD-1和CTLA-4通路）来治疗癌症的核心原理。这两次诺奖共同突显了免疫调控在癌症治疗中的里程碑意义：2018年的工作聚焦于解除T细胞上的“抑制信号”，而2025年的发现则强调Tregs在整体免疫平衡中的作用，二者结合为现代免疫疗法提供了从基础机制到临床应用的坚实基础。 ▲ 图1. 两次诺贝尔生理学或医学奖 ▼ 表1. 两次诺贝尔生理或医学奖 在关键维度的简要比较 诺贝尔奖对T细胞调控的认可强调了基础免疫学在肿瘤免疫治疗（IO）中的重要性。通过理解Tregs在免疫平衡中的作用，研究者可精准设计Treg抑制剂或增强剂，推动IO从单一检查点阻断向多靶点协同演进，以解决耐药性和低应答率问题。此外，IO靶点通过调节免疫系统活性，在抗肿瘤和自体免疫疾病中发挥相反作用：激活免疫用于抗肿瘤，抑制免疫用于自体免疫病。肿瘤免疫治疗已成为全球药物研发与投资的焦点，预计市场规模将从2024年的137.42亿美元增长至2033年的2960.1亿美元。本文将探讨免疫检查点抑制剂（ICI）及新兴靶点（如LAG-3、VEGF）的机制和挑战，结合Tregs研究分析如何通过调节免疫耐受逃避免疫清除，并探讨协同治疗在提升疗效中的关键作用。 ▲ 图2. 全球肿瘤免疫治疗市场规模（十亿美元） 02 免疫检查点抑制剂：经典的“刹车松动”策略 免疫系统的平衡至关重要。作为核心“战士”的T细胞，其活化需要双重信号：一是T细胞受体（TCR）识别抗原呈递细胞（APC）上的抗原-MHC复合物，二是共刺激信号（如CD28与B7结合）。与此同时，免疫系统还设有多重“刹车”机制——即免疫检查点——以防止过度活化及自身免疫损伤。免疫检查点抑制剂的作用正是解除这类刹车，从而增强T细胞对癌细胞的攻击能力。 01 CTLA-4：先驱者的挑战与新策略 CTLA-4是首个成功靶向的免疫检查点，位于T细胞表面，通过与B7分子结合抑制CD28的共刺激作用，防止T细胞过度活化。2011年，CTLA-4抑制剂伊匹木单抗（Yervoy®）获FDA批准，用于晚期黑色素瘤，开启了肿瘤免疫治疗的新纪元。然而，高毒性限制了其应用。当前的研究通过差异化策略，如局部给药和新作用机制，旨在提升疗效并降低毒性。新型HL12/HL32抗体通过避免降解、减少Treg耗竭和增强抗肿瘤作用，提出了更安全的治疗方案。此外，低剂量联用、抗体偶联药物（ADCs）和双特异性抗体等新技术，优化了CTLA-4抑制剂的治疗窗口，增强了与PD-1抑制剂联合使用时的协同抗癌效果。 ▲ 图3. CTLA4阻断抗体的效果 02 PD-1/PD-L1：时代里程碑的差异化新策略 PD-1/PD-L1抑制剂是肿瘤免疫治疗的核心，能够通过阻断肿瘤的免疫逃逸机制，恢复T细胞的抗癌功能。自2014年获批以来，这类药物取得了显著成果，但耐药性问题仍限制其广泛应用。为突破这一瓶颈，新一代PD-1/PD-L1药物正在朝着精细化方向发展，力求提高疗效并拓宽适应人群。研究者正在探索与PD-1/PD-L1不同表位结合的抗体，并通过工程化改造增强抗体依赖性细胞毒性（ADCC），实现双重抗癌效果。同时，针对PD-1的抗体设计了Fc silent结构（如IgG4/S228P），避免非期望性清除活化T细胞。此外，组合疗法与局部给药策略正在发展，结合其他免疫检查点抑制剂或靶向治疗，或通过局部高浓度给药，以进一步提升疗效并减少全身副作用。 ▲ 图4. PD-1/PD-L1阻断抗体的效果 03 打破肿瘤的免疫屏障：从诺奖发现到Tregs靶向疗法 调节性T细胞（Tregs）作为“和平卫士”，在肿瘤免疫疗法中一直是关键靶点。2025年诺贝尔奖肯定了Tregs在免疫耐受中的核心作用，推动了相关研究的进展。许多肿瘤通过诱导和富集Tregs，构建免疫屏障，抑制效应T细胞的攻击。因此，如何精准调控或削弱这些肿瘤“招安”的Tregs，成为免疫治疗的重要突破口。 直接靶向Tregs的抗体药物最具针对性，常通过识别Tregs特异性表面分子（如CCR8、CD25、OX40）选择性地耗竭肿瘤微环境中的免疫抑制细胞，恢复效应T细胞的活性。例如，anti-CCR8抗体DT-7012和CHS-114正在临床试验中评估其在实体瘤中的安全性与疗效。同时，CD25靶向的抗体药物偶联物（如PF-08046032）能够精确清除Tregs，减少对效应T细胞的干扰。然而，直接靶向Tregs的挑战在于平衡疗效与安全性，避免破坏外周免疫耐受，防止引发自身免疫反应。 间接靶向Tregs的药物通过干扰其信号通路或功能来削弱抑制作用。经典免疫检查点抑制剂如抗CTLA-4和PD-1/PD-L1药物，能削弱Tregs功能，增强效应T细胞活性。新兴靶点如TIGIT抗体（tiragolumab）进一步增强免疫反应。虽然这些策略安全性较高，但通常需要与直接靶向疗法联合使用，以实现更显著的抗肿瘤效果。 ▲ 图5. 靶向调节性T细胞 (Treg) 的抗肿瘤疗法 04 TCE疗法：精准“搭桥”，激活肿瘤免疫 T细胞衔接器（T-cell Engager, TCE）是肿瘤免疫疗法中的一项革命性突破。其本质是一种双特异性抗体，如同一个“分子桥梁”，一端抓住免疫T细胞表面的CD3蛋白，另一端则精准识别并结合肿瘤细胞表面的特定抗原（Tumor-Associated Antigen, TAA）。通过这种物理上的强制连接，TCE能绕过传统的免疫识别步骤，直接将T细胞引导至癌细胞旁，并强效激活T细胞，使其释放细胞毒性颗粒，进而“精准引爆”，高效杀伤肿瘤。随着技术的成熟，TCE的研发正朝着高度差异化的方向发展，力求在提升疗效的同时，扩大应用范围并优化安全性。目前的差异化主要体现在以下几个方面： 1) 靶点拓展与创新：早期TCE主要靶向血液肿瘤，如CD19和BCMA，而如今研发已进入实体瘤领域，探索如GPRC5D、Claudin 18.2等新靶点，攻克实体瘤治疗难题。 2) 分子结构优化：新一代TCE采用接近天然IgG的结构，显著延长体内半衰期，支持间歇性给药，并通过“静音”改造Fc片段，减少免疫激活，降低细胞因子释放综合征（CRS）等副作用。 3) 多特异性与条件性激活：最前沿的三特异性抗体，除连接T细胞和肿瘤细胞外，还结合肿瘤微环境中的蛋白，实现更精准的靶向。同时，“前药”设计使TCE仅在肿瘤富集的特定环境下激活，扩展了治疗窗口。 4) 强弱CD3设计：选择CD3结合强度影响药物的活性与安全性。强效CD3策略快速激活T细胞，但增加CRS风险；弱效CD3策略温和激活T细胞，减少毒性，特别是在实体瘤治疗中展现出巨大潜力。 总之，TCE疗法正在从单一的“搭桥”功能，发展为集靶点创新、结构优化与智能激活于一体的高度定制化治疗平台。 ▲ 图6. T细胞衔接器(TCE)通过抗原结合发挥作用 ▼ 表2. T细胞衔接器 (TCE) 上市药物一览 (截至2025年9月) 05 新兴靶点：下一代免疫疗法的希望与挑战 随着肿瘤免疫治疗的进展，免疫检查点抑制剂已取得显著疗效，但单一治疗策略面临耐药性和免疫逃逸等挑战。为突破这些局限，研究者积极探索联合免疫靶点或双特异性、三特异性抗体策略，以增强免疫系统对肿瘤的清除能力。以下是几种受关注的创新方案，展示了下一代免疫疗法的希望与挑战。 01 PD-1与CTLA-4：先驱者的新策略 将PD-1与CTLA-4同时阻断，标志着肿瘤免疫治疗的重要里程碑。CTLA-4在T细胞启动阶段发挥抑制作用，而PD-1在肿瘤微环境中抑制已激活的T细胞。联合使用可以在不同免疫环节解除抑制，增强抗肿瘤免疫。然而，临床上仍存在耐药性问题，且免疫相关不良事件发生率较高。为此，研究者开发了双特异性抗体，如XmAb20717（Vudalimab），该药物整合了PD-1和CTLA-4的作用机制，正进入临床试验（NCT05005728，NCT05032040），并报告了抗肿瘤活性信号。 02 PD-1与VEGF：当红炸子鸡 PD-1与VEGF联合治疗，尤其是PD-1 x VEGF双特异性抗体，近年来成为肿瘤免疫治疗的热点。VEGF通过促进肿瘤血管异常增生和免疫抑制微环境的形成，助长肿瘤生长。PD-1 x VEGF双抗不仅能抑制VEGF，正常化肿瘤血管，还能通过PD-1抑制解除T细胞的免疫抑制，增强免疫对肿瘤的杀伤力。AK112（Ivonescimab）是PD-1 + VEGF双特异性抗体，已在中国获批上市，主要用于特定类型的非小细胞肺癌（NSCLC）。该药物在多个临床试验中展示了良好的疗效和安全性，进一步验证了PD-1/VEGF双抗在多个癌种中的潜力。 ▲ 图7. Ivonescimab作用机制图 03 PD-1与LAG-3：联合的免疫解放 PD-1与LAG-3联合使用正成为免疫治疗领域的新亮点。LAG-3是一种与PD-1类似的免疫抑制性受体，通过抑制T细胞的活化，促进肿瘤免疫逃逸。联合抑制PD-1和LAG-3可以彻底解除T细胞的抑制，恢复其抗肿瘤活性。Tebotelimab（MGD013）是PD-1与LAG-3的双特异性抗体，已进入I/II期临床试验（NCT03219268），早期试验显示良好的疗效。这一组合疗法有望在临床治疗中发挥重要作用。 04 PD-1与其他靶点：突破耐药机制的双特异性抗体与三特异性抗体 新一代双靶点和三靶点抗体正成为肿瘤免疫治疗的重要突破，尤其在解决耐药性方面。PD-1 x IL-2、PD-1 x TGF-β和PD-1 x 4-1BB等双抗组合，分别通过增强T细胞活性、克服基质屏障和加速T细胞增殖，显著提升抗肿瘤效果。这些组合疗法正在快速推进临床试验，展现出解决耐药性和提高治疗响应率的巨大潜力。以CS2009（三特异性抗体）为例，它同时靶向PD-1、CTLA-4和VEGF，改善了T细胞功能、抑制免疫抑制微环境并优化肿瘤血管结构，为肿瘤免疫治疗带来新的突破。 ▼ 表3. PD-1/L1部分双抗药物 05 IO靶点在自体免疫疾病中的潜力 自免疾病通常伴随免疫系统的过度激活或失调，而通过靶向免疫检查点（如CTLA-4、PD-1/PD-L1、TIGIT等），可以抑制异常免疫反应，减少免疫系统对自身组织的攻击。这种策略的目的是通过调节免疫系统的活动来缓解自免疾病的症状，减轻患者的病情。然而，使用IO靶点治疗自免疾病也面临一些挑战，尤其是免疫检查点抑制剂（如PD-1/PD-L1抑制剂）可能会引起免疫相关的不良事件（irAEs），甚至加剧某些自免疾病。因此，如何平衡免疫激活和免疫抑制的效果，是该领域研究的一个关键。 ▼ 表4. 部分IO靶点自免相关管线 06 未来展望与挑战：持续进化的免疫治疗蓝图 1) 挑战：耐药性与生物标志物的探索 尽管免疫治疗取得了显著进展，但仍面临两大挑战：原发性耐药（初始无应答）和获得性耐药（治疗后出现进展）。现有的生物标志物（如PD-L1表达）对疗效预测的能力有限。因此，开发更可靠、预测性更强的生物标志物，以精准筛选获益人群，是未来研究的关键。2) 联合治疗的未来：从ICI-ICI到多模式协同未来免疫治疗将不再局限于ICI之间的联合，而是趋向于多模式协同治疗，通过结合不同机制的疗法实现“1+1>2”的效果。具体策略包括： ◐ 免疫+化疗或放疗：破坏肿瘤结构、增加抗原释放并清除免疫抑制细胞，为免疫药物创造更有利的微环境。 ◐ 免疫+靶向药物：抑制肿瘤生长并改善免疫微环境，从而增强治疗效果。 这种多维抗癌策略通过不同治疗方式的协同作用，提升疗效。3) 其它免疫疗法：协同作用的广阔前景 免疫抗体药物是核心，而其他新兴疗法则可成为重要的协同力量： ◐ 细胞疗法：CAR-T在血液肿瘤中成效显著，并正逐步探索实体瘤应用。 ◐ 抗体偶联药物（ADC）：精准递送化疗药物或毒素至癌细胞，与免疫疗法联用具有巨大潜力。 ◐ 寡核苷酸偶联抗体（AOC）：将寡核苷酸精准递送至肿瘤微环境中的免疫细胞或癌细胞，特异性沉默免疫抑制基因，克服传统免疫疗法的耐药性。▶ 总结 肿瘤免疫抗体药物已从前沿理念发展为癌症治疗的核心支柱，取得了里程碑式的进展。从CTLA-4抑制剂到PD-1/PD-L1药物，再到新靶点的涌现，每一步突破都为患者带来了新的希望。未来免疫治疗将走向多模式、协同化的“组合交响”，重点将放在克服耐药、优化生物标志物及探索更高效的联合策略，以实现个体化的精准治疗。 Sanyou 10th Anniversary: Analysis of the 2025 and 2018 Double Nobel Prizes Won in the Field of “Tumor Immunology” 01 Introduction: The Rise of Antibody-Based Cancer Immunotherapy In humanity's epic battle against cancer, treatments are undergoing a profound transformation—from the era of traditional surgery, radiotherapy, and chemotherapy to precise molecular targeted therapies, and now to antibody-based cancer immunotherapy, centered on harnessing the body's immune system as its primary defense. The 2025 Nobel Prize in Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell, and Shimon Sakaguchi for revealing regulatory T cells' (Tregs) role in peripheral immune tolerance. This foundational work explains how the immune system avoids attacking healthy tissues, spurring cancer immunotherapy development. The insights have sparked antibody drugs to deplete these cells, with many in clinical trials.This award resonates with the 2018 Nobel to James P. Allison and Tasuku Honjo for discovering cancer treatment through inhibiting immune negative regulators, particularly the PD-1 and CTLA-4 pathways. Together, the prizes highlight immune modulation's pivotal role in oncology: 2018 emphasized removing "inhibitory signals" from T cells, while 2025 spotlights Tregs' balancing act in the immune system. Their synergy creates a solid foundation—from basic mechanisms to clinical applications—for contemporary antibody-driven immunotherapy. ▲ Figure 1. Two Nobel Prizes in Physiology or Medicine  ▼ Table 1. Brief Comparison of the Two Nobel Prizes in Key Dimensions The Nobel Prize recognition of T-cell regulation highlights the importance of basic immunology in cancer immunotherapy (IO). By understanding the role of Tregs in immune balance, researchers can design targeted Treg inhibitors or enhancers, driving IO’s evolution from single checkpoint blockade to multi-target synergy to address resistance and low response rates. Additionally, IO targets modulate immune system activity, playing opposing roles in tumor immunity and autoimmune diseases—activating immunity for cancer and suppressing it for autoimmune disorders. Cancer immunotherapy has become a global focus in drug development and investment, with the market expected to grow from $13.742 billion in 2024 to $296.01 billion by 2033. This article explores the mechanisms and challenges of immune checkpoint inhibitors (ICIs) and emerging targets (like LAG-3, VEGF), analyzing how Tregs influence immune tolerance and immune evasion, and discusses the critical role of combination therapies in enhancing efficacy. ▲ Figure 2. Global Cancer Immunotherapy Market Size 02 Immune Checkpoint Inhibitors: The Classical “Release the Brakes” Strategy Immune system balance is vital. T cells, the core “fighters” of immunity, require two signals for activation: recognition of the antigen–MHC complex on antigen-presenting cells (APCs) by the T-cell receptor (TCR), and a co-stimulatory signal such as CD28 binding to B7. Meanwhile, the immune system employs multiple “brakes,” known as immune checkpoints, to prevent overactivation and autoimmune damage. Immune checkpoint inhibitors work by releasing these brakes, thereby boosting T-cell activity against cancer cells. 01 CTLA-4: Challenges and New Strategies for a Pioneer CTLA-4, the first successfully targeted immune checkpoint, inhibits CD28 co-stimulation by binding to B7 molecules on T cells to prevent overactivation. The CTLA-4 inhibitor ipilimumab (Yervoy®), approved by the FDA in 2011 for advanced melanoma, marked a new era in cancer immunotherapy but showed high toxicity. Current strategies—such as localized delivery, novel antibodies (HL12, HL32), low-dose combinations, ADCs, and bispecific antibodies—aim to enhance efficacy, reduce toxicity, and improve synergy with PD-1 inhibitors. ▲ Figure 3. Effects of CTLA-4 Blocking Antibodies 02 PD-1/PD-L1: An Era Milestone and Pathways for Differentiated Innovation PD-1/PD-L1 inhibitors are the cornerstone of cancer immunotherapy, blocking tumor immune evasion and restoring T-cell antitumor activity. Since their approval in 2014, these drugs have achieved remarkable success, though resistance remains a major challenge. To overcome this, next-generation PD-1/PD-L1 therapies are becoming more refined, aiming to enhance efficacy and expand patient benefit. Researchers are developing antibodies that bind distinct PD-1/PD-L1 epitopes and engineering them to boost antibody-dependent cellular cytotoxicity (ADCC) for dual antitumor effects. Meanwhile, Fc-silent antibody designs (such as IgG4/S228P) help avoid unwanted depletion of activated T cells. Combination approaches and localized delivery strategies—pairing PD-1/PD-L1 inhibitors with other checkpoint or targeted therapies, or applying them directly at tumor sites—are also advancing to improve outcomes while minimizing systemic side effects. ▲ Figure 4. Effects of PD-1/PD-L1 Blocking Antibodies 03 Overcoming Tumor Immune Suppression: From Nobel Discoveries to Treg-Targeted Therapies Regulatory T cells (Tregs), known as the "guardians" are key targets in cancer immunotherapy. The 2025 Nobel Prize highlighted their central role in immune tolerance, accelerating related research. Many tumors induce and enrich Tregs to build immune barriers that suppress effector T cell attacks. Thus, precisely modulating or weakening these tumor "recruited" Tregs has become a critical breakthrough for immunotherapy. Antibody drugs that directly target Tregs are among the most focused strategies. They work by recognizing surface molecules unique to Tregs — such as CCR8, CD25, or OX40 — and selectively clearing out the suppressive cells within tumors. For instance, anti-CCR8 antibodies like DT-7012 and CHS-114 are now in clinical trials for solid cancers, while CD25-targeting antibody–drug conjugates (e.g., PF-08046032) precisely remove Tregs without overly disturbing other immune cells. The main challenge is striking the right balance: boosting anti-tumor immunity without tipping the system into autoimmunity. Indirect strategies, including anti-CTLA-4, anti-PD-1/PD-L1, and TIGIT antibodies (like tiragolumab), suppress Treg function while enhancing effector T-cell responses. These approaches are generally safer but often work best in combination with direct Treg-targeting therapies for stronger, more durable antitumor effects. ▲ Figure 5. Antitumor Therapies Targeting Regulatory T Cells (Tregs) 04 TCE Therapy: Precision "Bridging" to Activate Tumor Immunity T-cell Engagers (TCEs) are a groundbreaking innovation in tumor immunotherapy. These bispecific antibodies precisely connect T cells with tumor cells, activating the T cells to directly kill tumors. One end of the TCE binds to CD3 on T cells, while the other attaches to tumor-associated antigens (TAAs) on cancer cells, bypassing traditional immune recognition to rapidly trigger T-cell activation and release cytotoxic particles for efficient tumor destruction. As the technology advances, TCEs are evolving in the following key areas: 1) Target Expansion and Innovation: Early TCEs targeted blood cancers (CD19, BCMA), now extending to solid tumors with novel targets like GPRC5D and Claudin 18.2. 2) Molecular Structure Optimization: Next-gen TCEs mimic natural IgG for longer half-life, support intermittent dosing, and reduce side effects (e.g., CRS) with Fc modifications. 3) Multispecific and Conditional Activation: Trispecific antibodies improve targeting by binding both tumor cells and the tumor microenvironment, while "prodrug" designs activate TCEs only in tumor-rich areas. 4) Strong vs. Weak CD3 Binding: Strong CD3 engagement rapidly activates T cells but increases CRS risk; weak engagement reduces toxicity, particularly in solid tumor treatments.In summary, TCE therapy is evolving from a simple “bridging” tool into a highly customized treatment platform, integrating target innovation, structural optimization, and intelligent activation. ▲ Figure 6. Mechanism of Action of T-cell Engagers (TCEs) via Antigen Binding ▼ Table 2. Approved T-cell Engager (TCE) Therapies (as of October 2025) 05 Emerging Targets: Opportunities and Challenges for Next-Generation Immunotherapies With advances in cancer immunotherapy, checkpoint inhibitors have achieved great success but still face resistance and immune escape. To overcome these challenges, researchers are exploring combination therapies and multi-specific antibodies to enhance tumor clearance—showcasing both the promise and hurdles of next-generation immunotherapies. 01 PD-1 and CTLA-4: New Strategies for Pioneers Simultaneous blockade of PD-1 and CTLA-4 marked a major milestone in cancer immunotherapy. CTLA-4 suppresses T-cell activation during the priming phase, while PD-1 inhibits activated T cells within the tumor microenvironment. Their combination releases immune inhibition at multiple stages, enhancing anti-tumor immunity. However, resistance and high rates of immune-related adverse events remain challenges. To address this, bispecific antibodies such as XmAb20717 (Vudalimab) have been developed, integrating PD-1 and CTLA-4 mechanisms. The drug has entered clinical trials (NCT05005728, NCT05032040) and shown preliminary anti-tumor activity. 02 PD-1 × VEGF: The Hot Favorite Right Now VEGF promotes tumor angiogenesis and an immunosuppressive microenvironment. PD-1 × VEGF bispecifics inhibit VEGF to normalize tumor vasculature while restoring T-cell activity via PD-1 blockade, thereby enhancing tumor killing. AK112 (Ivonescimab), a PD-1/VEGF bispecific antibody, has been approved in China for specific non–small cell lung cancer (NSCLC) subtypes, demonstrating promising efficacy and safety across multiple clinical studies. ▲ Figure 7. Mechanism of Ivonescimab 03 PD-1 and LAG-3: Combined Checkpoint Blockade PD-1 and LAG-3 combination therapy is emerging as a new focus in immuno-oncology. LAG-3, an inhibitory receptor similar to PD-1, suppresses T-cell activation and promotes tumor immune evasion. Dual blockade of PD-1 and LAG-3 can fully restore T-cell antitumor activity. Tebotelimab (MGD013), a PD-1/LAG-3 bispecific antibody, is in phase I/II trials (NCT03219268) with encouraging early results, showing promise for future clinical application. 04 PD-1 and Other Targets: Bispecific and Trispecific Antibodies to Overcome Resistance Mechanisms Next-generation dual- and tri-specific antibodies are driving breakthroughs in cancer immunotherapy, especially against resistance. Combinations like PD-1 × IL-2, PD-1 × TGF-β, and PD-1 × 4-1BB enhance T-cell activity, overcome stromal barriers, and boost proliferation, markedly improving antitumor efficacy. Tri-specific CS2009, targeting PD-1, CTLA-4, and VEGF, enhances T-cell function, modulates the tumor microenvironment, and normalizes vasculature, showing strong clinical potential. ▼ Table 3. Selected PD-1/L1 Bispecific Antibodies 05 The Potential of IO Targets in Autoimmune Diseases Autoimmune diseases involve excessive or misdirected immune activity. Targeting immune checkpoints such as CTLA-4, PD-1/PD-L1, and TIGIT can help suppress abnormal responses and reduce self-tissue attack, easing symptoms. However, using IO targets also carries risks—checkpoint inhibitors may trigger immune-related side effects or worsen some conditions. Balancing immune activation and suppression remains a key challenge. ▼ Table 4. Pipeline of Selected IO Targeted Drugs 06 Future Outlook and Challenges: The Evolving Blueprint of Immunotherapy 1) Challenges: Resistance and Biomarker Exploration Despite remarkable progress in immunotherapy, two major challenges remain: primary resistance (lack of initial response) and acquired resistance (disease progression after treatment). Current biomarkers, such as PD-L1 expression, have limited predictive power. Therefore, developing more reliable and predictive biomarkers to accurately identify patients who will benefit is a key focus for future research. 2) The Future of Combination Therapy: From ICI-ICI to Multi-Modal Synergy Future immunotherapy will extend beyond combinations of immune checkpoint inhibitors (ICIs) toward multi-modal synergistic approaches that achieve a “1+1>2” effect by integrating therapies with different mechanisms. Key strategies include: ◐ Immunotherapy + Chemotherapy or Radiotherapy: Disrupting tumor structure, increasing antigen release, and eliminating immunosuppressive cells to create a more favorable microenvironment for immune agents. ◐ Immunotherapy + Targeted Therapy: Inhibiting tumor growth while improving the immune microenvironment to enhance overall efficacy.This multi-dimensional approach leverages the synergy of diverse treatments to achieve stronger and more durable anti-cancer effects. 3) Other Immunotherapies: New Frontiers in Synergistic Potential While immune antibody drugs remain the cornerstone, emerging therapies are becoming powerful allies： ◐ Cell therapies such as CAR-T have achieved remarkable success in hematologic cancers and are being explored for solid tumors. ◐ Antibody-drug conjugates (ADCs) precisely deliver chemotherapeutic agents or toxins to cancer cells, offering great potential when combined with immunotherapy. ◐ Antibody-oligonucleotide conjugates (AOCs) enable targeted delivery of oligonucleotides to immune or cancer cells within the tumor microenvironment, selectively silencing immunosuppressive genes and helping to overcome resistance to traditional immunotherapies. ▶ Summary Cancer immunotherapy antibodies have evolved from groundbreaking concepts to become a cornerstone in cancer treatment, achieving milestone progress. From CTLA-4 inhibitors to PD-1/PD-L1 drugs, and the emergence of new targets, each breakthrough brings new hope for patients. The future of immunotherapy will focus on multi-modal, synergistic "combination symphonies," with an emphasis on overcoming resistance, optimizing biomarkers, and exploring more efficient combination strategies to achieve personalized precision treatment. ▶ Reference 1. Hsu CY, Pallathadka H, Jasim SA, et al. Innovations in cancer immunotherapy: A comprehensive overview of recent breakthroughs and future directions. Crit Rev Oncol Hematol. 2025;206:104588. doi:10.1016/j.critrevonc.2024.104588 2. Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z. PD-1/PD-L1 Checkpoint Inhibitors in Tumor Immunotherapy. Front Pharmacol. 2021;12:731798. Published 2021 Sep 1. doi:10.3389/fphar.2021.731798 3. Nova One Advisor. Cancer immunotherapy market size, share & trends analysis report, by product, by application, by distribution, by end use, by region: Global industry analysis, size, share, growth, trends, regional outlook, and forecast 2024-2033. Nova One Advisor website. Published April 2025. 4. Grand View Research. Asia Pacific cancer immunotherapy market outlook, 2024 - 2030. Grand View Research. Published 2024. Accessed September 21, 2025. 5. Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol. 2023;14:1167975. Published 2023 May 25. doi:10.3389/fimmu.2023.1167975 6. Babamohamadi M, Mohammadi N, Faryadi E, et al. Anti-CTLA-4 nanobody as a promising approach in cancer immunotherapy. Cell Death Dis. 2024;15(1):17. Published 2024 Jan 8. doi:10.1038/s41419-023-06391-x 7. Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651-668. doi:10.1038/s41577-020-0306-5 8. Pasqualotto E, Moraes FCA, Chavez MP, et al. PD-1/PD-L1 Inhibitors plus Chemotherapy Versus Chemotherapy Alone for Resectable Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Cancers (Basel). 2023;15(21):5143. Published 2023 Oct 26. doi:10.3390/cancers15215143 9. Parvez A, Choudhary F, Mudgal P, et al. PD-1 and PD-L1: architects of immune symphony and immunotherapy breakthroughs in cancer treatment. Front Immunol. 2023;14:1296341. Published 2023 Dec 1. doi:10.3389/fimmu.2023.1296341 10. Cheng W, Kang K, Zhao A, Wu Y. Dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in lung cancer. J Hematol Oncol. 2024;17(1):54. Published 2024 Jul 27. doi:10.1186/s13045-024-01581-2 11. Esfandiari A, et al. T-cell engaging bispecific antibodies in cancer therapy: limitations, challenges, and opportunities. Mol Ther. 2024. 12. Labrijn AF, et al. T cell-engaging bispecific antibodies in cancer immunotherapy. Nat Rev Clin Oncol. 2022. 13. Mazor Y, et al. Diversifying the T cell-engaging bispecific antibody platform. Nat Rev Drug Discov. 2021. 14. Cech P, Skórka K, Dziki L, Giannopoulos K. T-Cell Engagers-The Structure and Functional Principle and Application in Hematological Malignancies. Cancers (Basel). 2024;16(8):1580. Published 2024 Apr 20. doi:10.3390/cancers16081580 15. Cheng B, Lv J, Xiao Y, Song C, Chen J, Shao C. Small molecule inhibitors targeting PD-L1, CTLA4, VISTA, TIM-3, and LAG3 for cancer immunotherapy (2020-2024). Eur J Med Chem. 2025;283:117141. doi:10.1016/j.ejmech.2024.117141 16. Luke JJ, Patel MR, Blumenschein GR, et al. The PD-1- and LAG-3-targeting bispecific molecule tebotelimab in solid tumors and hematologic cancers: a phase 1 trial. Nat Med. 2023;29(11):2814-2824. doi:10.1038/s41591-023-02593-0 17. Chao MP, Takimoto CH, Feng DD, et al. Therapeutic Targeting of the Macrophage Immune Checkpoint CD47 in Myeloid Malignancies. Front Oncol. 2020;9:1380. Published 2020 Jan 22. doi:10.3389/fonc.2019.01380 18. Gomes de Morais AL, Cerdá S, de Miguel M. New Checkpoint Inhibitors on the Road: Targeting TIM-3 in Solid Tumors. Curr Oncol Rep. 2022;24(5):651-658. doi:10.1007/s11912-022-01218-y 19. Hodi FS, Chapman PB, Sznol M, et al. Safety and efficacy of combination nivolumab plus ipilimumab in patients with advanced melanoma: results from a North American expanded access program (CheckMate 218). Melanoma Res. 2021;31(1):67-75. doi:10.1097/CMR.0000000000000708 20. Xu J, Shen J, Gu S, et al. Camrelizumab in Combination with Apatinib in Patients with Advanced Hepatocellular Carcinoma (RESCUE): A Nonrandomized, Open-label, Phase II Trial.Clin Cancer Res. 2021;27(4):1003-1011. doi:10.1158/1078-0432.CCR-20-2571 21. Fitzgerald KN, Lee CH, Voss MH, et al. Cabozantinib Plus Nivolumab in Patients with Non-Clear Cell Renal Cell Carcinoma: Updated Results from a Phase 2 Trial. Eur Urol. 2024;86(2):90-94. doi:10.1016/j.eururo.2024.04.025 1 推荐阅读 三优十周年｜TCE药物-重塑免疫治疗版图的新力量 三优十周年｜神经系统疾病治疗进展 三优十周年｜AI-STAL 智能超万亿分子库发展历程 三优十周年｜打造全球顶尖的原创新药创新工场 三优十周年｜抗体治疗50年风雨江湖 三优十周年｜针对宠物疾病的单克隆抗体药物 三优十周年｜CAR-T细胞治疗现状挑战与未来 三优十周年｜服务篇-体外药效筛选解决方案 三优十周年｜AI-STAL篇-Anticalin靶向蛋白库 三优十周年｜靶点篇-自身免疫疾病靶点介绍 创新前沿｜三优生物类器官产学研联盟启航 中和抗体“硬核出击”，斩断CHIKV病毒感染链 三优十周年｜服务篇-靶点至PCC药物研发 三优十周年｜靶点篇-六大恶性肿瘤靶点介绍创新前沿｜2025ADC热门靶点与技术创新启示 关于三优生物 三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。 公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。 1 推荐阅读 三优十周年｜TCE药物-重塑免疫治疗版图的新力量 三优十周年｜神经系统疾病治疗进展 三优十周年｜AI-STAL 智能超万亿分子库发展历程 三优十周年｜打造全球顶尖的原创新药创新工场 三优十周年｜抗体治疗50年风雨江湖 三优十周年｜针对宠物疾病的单克隆抗体药物 三优十周年｜CAR-T细胞治疗现状挑战与未来 三优十周年｜服务篇-体外药效筛选解决方案 三优十周年｜AI-STAL篇-Anticalin靶向蛋白库 三优十周年｜靶点篇-自身免疫疾病靶点介绍 创新前沿｜三优生物类器官产学研联盟启航 中和抗体“硬核出击”，斩断CHIKV病毒感染链 三优十周年｜服务篇-靶点至PCC药物研发 三优十周年｜靶点篇-六大恶性肿瘤靶点介绍创新前沿｜2025ADC热门靶点与技术创新启示 关于三优生物 三优生物是一家以“让天下没有难做的创新生物药”为使命，以超万亿分子库和智能科技驱动的生物医药高科技企业。 公司致力于打造全球顶尖的原创新药创新工场。公司以智能超万亿分子库（AI-STAL）为核心；以干湿结合、国际领先的创新生物药智能化及一体化研发平台为依托；以多样化的业务模式推动全球创新药物的研发及产业化。 公司总部位于中国上海，在亚洲、北美洲、欧洲等多地建立了业务中心，形成了全球化的业务网络，现有投产及布局的研发及GMP场地20000多平方米。 公司已与全球2000多家药企、生技公司等建立了良好的合作关系，已赋能1200多个新药研发项目；已完成50多个合作研发项目，其中10多个协同研发项目已推至IND及临床研发阶段。 公司已申请130多项发明专利，其中30多项发明专利已获得授权，并获得了国家级高新技术企业、上海市专精特新、ISO9001、ISO27001等10余项资质及体系认证。