扶正解毒化瘀法对免疫治疗减毒增效作用的研究进展
作者简介:
陈昱帆，女，硕士，主要从事中西医结合肿瘤防治，ORCID: 0000-0002-9301-6188
冯利: 国家癌症中心/中国医学科学院肿瘤医院中医科主任，主任医师，教授，北京协和医学院博士后及博士研究生导师，北京中医药大学及中国中医科学院博士研究生导师。全国著名中医、中西医结合肿瘤治疗专家，中央保健会诊专家，国家中医药管理局第七批全国老中医药专家学术经验继承指导老师，国家中医药管理局第三批“全国优秀中医临床人才”，北京市中西医结合肿瘤防治国际合作基地（中心）负责人，国家中医药管理局及北京市中医管理局中西医协同“旗舰科室”带头人。主要从事恶性肿瘤及并发症的临床及基础研究，发表SCI及中文核心论文100余篇，主编学术专著3部，主编及参编指南15部，获批发明专利4项，承担国家重点研发计划项目、国家自然科学基金面上项目、北京市自然科学基金面上项目等多项国家和省部级研究课题
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通讯作者:
Research Progress of Fuzheng Jiedu Huayu Method in Reducing Toxicity and Enhancing Efficacy of Immunotherapy
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摘要:
近年来免疫治疗在肿瘤领域中持续取得重大突破。免疫治疗主要包括免疫检查点抑制剂、肿瘤疫苗治疗、溶瘤病毒治疗和过继细胞治疗。阻断程序性死亡受体1（PD-1）或程序性死亡配体1（PD-L1）的免疫检查点抑制剂已经纳入非小细胞肺癌、恶性黑色素瘤等晚期实体瘤的一线临床治疗。然而肿瘤原发或继发性的耐药严重限制了患者的生存获益，肺炎、甲状腺功能减退、垂体炎、心肌炎等免疫治疗相关不良反应也在很大程度上影响了患者的生活质量。“扶正解毒化瘀”抗癌理论是指导中医药防治肿瘤的重要理念，也是中医药对免疫治疗发挥减毒增效作用的重要治法治则。本文通过总结免疫治疗研究进展、从“扶正解毒化瘀”理论出发，论述中医药对免疫治疗减毒增效的机制，以期为中医协同肿瘤免疫治疗提供参考。
Abstract:Immunotherapy, including immune checkpoint inhibitors, tumor vaccine therapy, oncolytic virotherapy, and adoptive cell therapy, has made remarkably breakthroughs in the field of oncology. Immune checkpoint inhibitors, which block programmed death receptor 1 or programmed death ligand 1, have been included in the first-line clinical treatment for advanced solid tumors, such as non-small cell lung cancer and malignant melanoma. However, primary or secondary drug resistance in tumors severely limits the survival benefits for patients. Immune-related adverse reactions, such as pneumonia, hypothyroidism, hypophysitis, and myocarditis, also greatly affect the quality of life of patients. Fuzheng Jiedu Huayu is an important concept guiding the prevention and treatment of tumors with traditional Chinese medicine (TCM). It is also a curative principle and therapeutic TCM method to reduce the toxicity and enhance the efficacy of immunotherapy. This article summarizes the research progress of immunotherapy and discusses how TCM reduces the toxicity and enhances the efficacy of immunotherapy, hoping to provide a reference for the integrated treatment of tumors with TCM and immunotherapy.
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0 引言
癌症作为全球主要死因之一，其发病率和死亡率仍呈现出居高不下的趋势，中国在全球的癌症新发和死亡人数均居首位[1]，形势严峻。癌症免疫治疗发展迅速、前景良好，与之相关的研究目的大多是在增强免疫治疗疗效的同时减少免疫相关不良事件（Immune-related adverse events, irAE）的发生。诸多研究表明，在中医“扶正化瘀解毒”思想指导下配伍的方剂、单味中药及提取物能对免疫治疗发挥减毒增效的作用[2]，该理论对癌症免疫治疗的疗效、不良反应和预后的纵深管理具有重要指导作用，蕴含其中的现代药理学机制也浮现冰山一角。本文将梳理总结“扶正化瘀解毒”相关中医药对免疫治疗的疗效和减毒增效机制，以期为免疫治疗的中西医协同干预提供启示。
1 现代免疫治疗概述
癌症免疫治疗是近年来肿瘤治疗领域的一项革命性进展，主要激活人体免疫系统中CD8+T细胞对肿瘤细胞的杀伤作用，抑制肿瘤细胞的免疫逃逸。近年来，癌症免疫治疗在临床治疗过程中发挥着日益重要的作用，其疗法根据作用机制的不同分为：（1）获取患者自身免疫细胞并在体外提升其抗肿瘤活性后重新输入患者体内的嵌合抗原受体T细胞（Chimeric antigen receptor T-cell immunotherapy, CAR-T）疗法、T细胞受体嵌合T细胞（T cell receptor-T cell, TCR-T）免疫疗法[3]以及肿瘤浸润性淋巴细胞（Tumor infiltrating lymphocytes, TILs）免疫疗法；（2）利用肿瘤抗原激活免疫细胞的肿瘤疫苗[4]；（3）选择性利用病毒在肿瘤细胞内复制导致细胞凋亡，同时具有与其他癌症治疗方法联合应用[5]的溶瘤病毒策略；（4）免疫检查点抑制剂（Immune checkpoint inhibitors, ICI）。
免疫检查点抑制剂是免疫治疗的现代里程碑，主要包括程序性死亡受体1（Programmed cell death protein 1, PD-1）单抗（例如纳武利尤单抗、帕博利珠单抗和西米普利单抗）、程序性死亡受体-配体1（Programmed cell death-ligand 1, PD-L1）单抗（例如阿替利珠单抗、度伐利尤单抗和阿维鲁单抗）以及抗细胞毒性T淋巴细胞相关蛋白4（Cytotoxic T-lymphocyte associated protein 4, CTLA-4）单抗（例如伊匹木单抗）。
PD-1作为一种凋亡相关分子，其抗原在活化的胸腺细胞或脾脏T细胞中高表达[6]，PD-L1是其在肿瘤微环境中表达的主要配体，可以诱导细胞毒性T细胞耗竭，抑制其对肿瘤的杀伤作用。CTLA-4作为T细胞表面的一种跨膜受体，通过与抗原呈递细胞（Antigen presenting cell, APC）上的配体结合以抑制细胞毒性T细胞激活[7]。CD80和CD86是T细胞的两种共刺激分子，均与CD28和CTLA-4受体相互作用，但CTLA-4对配体CD80和CD86的亲和力明显高于CD28[8]，导致同CD28竞争性抑制T细胞的活化，因此阻断CTLA-4可以增强T细胞的活性以发挥免疫抗癌作用。目前，抗PD-1/PD-L1单抗已经广泛用于非小细胞肺癌、尿路上皮癌、肝癌、恶性黑色素瘤、肾细胞癌、头颈部鳞癌等多种实体瘤的临床治疗[9-10]，伊匹木单抗也已于2011年成为美国食品药品监督管理局批准治疗转移性黑色素瘤的首个抗CTLA-4单抗[11]。
研究显示，尽管抗PD-1/PD-L1单抗在许多原发性肿瘤和软组织转移瘤的治疗中取得了成功，但与未转移的同癌种患者相比，在骨转移患者中应用抗PD-1/PD-L1单抗没有观察到相似的生存获益[12]。免疫检查点抑制剂仍存在致脱靶性、抗药性等潜在风险，需要选择其他治疗方式协同治疗。研究表明，一些中药提取物的有效成分具有抗PD-1/PD-L1或抗CTLA-4活性的协同抗癌作用[13]。
2 扶正解毒化瘀法与免疫治疗
2.1 扶正解毒化瘀法与免疫治疗结合的理论基础
宏观角度来看，肿瘤治疗的重点聚焦于扶正祛邪、调整阴阳平衡。在中医基础理论中，人体“正气”是对抗“癌毒”的主要力量，人体各系统的肿瘤都有可能因正气不足感毒而发，《景岳全书》中概述“毒归五脏，证有不同，当详辨也”，《外科正宗》有更详细的论述：“肝统筋......血燥筋挛曰筋瘤。心主血......火旺逼血沸腾，复被外邪所搏而肿曰血瘤。脾主肌肉......肌肉消薄，土气不行，逆于肉里而为肿曰肉瘤。肺主气......腠理不密，外寒搏而为肿曰气瘤。肾主骨......骨无荣养而为肿曰骨瘤”，可见肝心脾肺肾五脏脏气不足，及其所主部位也会成为气血薄弱之处，在外邪侵扰的作用下形成不同的癌肿，加之“人之气血循环，无滞瘿瘤之患”，故正虚毒蕴部位最易生肿瘤。
免疫治疗虽然能通过抑制CD8+细胞耗竭以发挥抗癌作用，但是其脱靶效应也会耗伤正气，导致自身免疫性的垂体炎、心肌炎、糖尿病，严重者可危及生命。患者可以因为脾气亏虚而出现气短乏力、神疲懒言等甲状腺功能减退相关症状，因心阳不足、气虚血瘀而出现心悸怔忡、胸闷胸痛等心肌炎相关症状，或因气阴两虚而出现口渴、多饮、多尿、消瘦等糖尿病相关症状。因此提倡扶正祛邪，通过补虚扶正、化瘀解毒的方式减缓肿瘤生长速度、提高患者机体活力，达到阴阳平衡的健康状态。这与现代医学在肿瘤免疫治疗领域的基本策略不谋而合，即通过增强免疫耐受减少免疫逃逸，提高患者生存质量。
微观角度来看，肿瘤微环境是肿瘤细胞与免疫细胞进行斗争的最直接的“战场”[14]。肿瘤的代谢过程中产生代谢废物和各种细胞因子、分泌介质的不同，使肿瘤微环境持续发生动态变化[15]，进而出现个体间和肿瘤内的异质性。因此，即便是同一癌种患者对免疫治疗的敏感性也存在较大的个体间和时间差异，需要定期评估当前免疫治疗方案的可行性加以调整，这与中医诊疗理念“辨证论治”“因人施治”的底层逻辑一致，协同免疫治疗将收获更好的临床疗效和预后结果。
2.2 从“虚-毒-瘀”的角度看免疫检查点相关不良反应
免疫检查点相关不良反应属中医“药毒”范畴。肿瘤患者多正虚，即机体存在气血阴阳亏虚的偏性。中医认为气主生血、行血、摄血，气虚时气的推动、化生血液作用减弱，可以导致血液运行不畅，形成血瘀；气不摄血时血液不归经，血液溢出脉络，形成瘀血；气虚可能导致水液代谢失调，产生痰湿，痰湿阻碍血液运行，导致血瘀，血瘀日久与痰湿搏结化生“癌毒”。“癌毒”打破正气中正平和的平衡状态后，机体对药物敏感性降低，更易受“药毒”耗伤，发生诸多不良反应。因此，气虚则正虚，导致血瘀，令肿物胶结难化；正虚则毒蕴，加重血瘀，使周身毒漫。综上可知，正虚毒蕴血瘀是导致免疫检查点相关不良反应的重要病理基础。
一项横断面研究表明[16]，110例非小细胞肺癌患者经帕博利珠单抗治疗的1年期间，疲乏是其治疗过程中最先出现的不良反应，发生率达90%，气虚质患者最常见，皮肤瘙痒多见于气虚质和阴虚质患者，阳虚质患者则腹泻多发。免疫检查点抑制剂相关肺炎（Checkpoint inhibitor-associated pneumonitis, CIP）被认为是一种特殊的免疫介导的间质性肺疾病，陈晨等认为CIP的中医病机为以肺气阴两虚，痰瘀阻肺，或肺肾两虚，治当扶正与通络为主[17]，其他免疫相关不良反应中医药研究详见表1。
表 1 免疫相关不良反应中医药研究成果汇总表Table 1 Researches of traditional Chinese medicine on immunotherapy-related adverse reactionsImmune-related
adverse effectsTraditional Chinese medicine Treatment
durationStudy
typeStudy
sampleStudy results Skin toxicity Clearing heat and removing dampness formula[18] (Si-Miao-Yong-An decoction +coix seed) For external use, up to a maximum of one month Retrospective cohort study 30 patients with grade 2-3 immune-related rash Among the patients, 13 who previously failed corticosteroid treatment experienced relief of pain symptoms associated with rashes after using the Clearing heat and removing dampness formula, with an overall effective rate of 70%. In all the patients, including those who had not previously received corticosteroid treatment, the median time for rashes to recover to grade 1 was 8 days, with a total effective rate of 80%. Nourishing yin and eliminating rash formula[19] Oral administration for two weeks Retrospective Cohort Study 25 patients with immune-related cutaneous adverse reactions Compared with no intervention and the use of hormone therapy, the combined treatment of Yin-nourishing and rash-reducing formula significantly alleviated the severity of rashes and feverish sensation in five centers and accelerated the rate of rash resolution. Jiedu Qingzhen formula[20] Continuous medication for
21 daysRandomized controlled
clinical trial72 patients with malignant tumors complicated with wind-heat sores treated with PD-1 inhibitors Compared with the management plan for immune-related skin adverse reactions recommended by the CSCO guidelines, the Jiedu Qingzhen formula significantly improved the grading of wind-heat sores, TCM syndromes, itching grading, KPS scores, and DLQI scores. Diarrhea Modified Sheng-Yang-Yi-Wei powder[21] / Randomized controlled
clinical trial60 patients with immune-related diarrhea due to malignant tumors of spleen yang deficiency syndrome at grades 2-3 Compared with those treated solely with Western medicine (toripalimab，, sintilimab, and camrelizumab), the patients who additionally received the modified Sheng-Yang-Yi-Wei powder treatment showed significant improvements in TCM syndrome scores (P<0.05) and a notable increase in KPS scores. Modified Chaihu Guizhi decoction[22] Continuous medication for
21 daysRandomized controlled
clinical trial92 cancer patients (including various types of cancer such as gallbladder cancer, lung cancer, and liver cancer) Compared with those under treatment plans that use only immunosuppressants, such as PD-1/PD-L1 inhibitors, the patients who additionally received modified Chaihu Guizhi decoction showed reduced incidence of colitis by 28% and improved diarrhea associated with PD-1 monoclonal antibody therapy. Colitis Wumei Pills[23] / Randomized controlled experiment
in ratsForty rats were randomly divided into five groups, with eight rats in each group Compared with that in the positive control group, the serum IL-1β expression was increased in the low- and high-dose Wumei Pill groups (P<0.05). The colonic IL-1β expression was decreased in both groups (P<0.05), indicating that Wumei Pill can ameliorate the pathological damage of immune colitis. Supplemented Shaoyao Decoction[24] For acute diarrhea, take medication continuously for 5 days; for chronic diarrhea, maintain treatment after the effect is shown. Randomized controlled
clinical trial80 patients with intestinal damp-heat type who developed colitis after immunotherapy Compared with loperamide alone, its combination with Shaoyao Decoction showed superior efficacy in improving the symptoms of acute and chronic diarrhea, abdominal pain, anal burning, and bitter taste in the mouth of patients with immune-related colitis. Hepatitis Ginsenoside Rd[25] / Cell experiments+
mouse experiments32 C57BL/6 mice were randomly divided into four groups, with eight mice in each group Ginsenoside Rd exerts a protective effect against immune hepatitis in mice by inhibiting the cGAS/STING/NLRP3 inflammasome signaling pathway. Cancer-Related Fatigue Qigui Buxue Syrup[26] A treatment cycle lasts for 21 days, with two cycles of treatment Randomized controlled clinical trial Fifty patients were enrolled and randomly divided into two groups Compared with the monotherapy of sintilimab, the combined treatment with Qigui Buxue Syrup can significantly improve the multidimensional fatigue status, TCM symptoms, and physical condition in patients with qi deficiency type advanced nonsmall cell lung cancer (NSCLC) after immunotherapy. It also enhances the efficacy of immunotherapy with a high safety profile. 目前已有四妙勇安汤、滋阴消疹方等方剂用于治疗免疫相关皮肤不良反应的研究报道。湿热之邪阻碍气血的正常运行，形成瘀血，血瘀则肌肤失去养分，导致皮肤问题。四妙勇安汤[18]清利湿热，以防热邪伤正，解毒活血以通络；热邪伤阴，外受药毒之邪，内外夹攻而生疹，解毒消疹方[20]清热生津以解药毒；阴虚血燥生风，常致皮疹迁延不愈，滋阴消疹方[19]祛风止痒，滋阴扶正以退疹。药毒伤脾，脾阳不振而湿浊淤滞，清谷不化，发为腹泻。加味升阳益胃散[21]诸药共奏益气升阳、清热除湿之效以止泻；柴胡桂枝汤[22]温脾散寒，疏利经脉以安肠道；若治疗过程中热邪灼伤阴液，酿液为痰，痰火窜扰，血气逆乱，肝脾失调导致结肠炎。乌梅丸[23]清热燥湿、清上温下，发挥涩肠止泻、缓急止痛的作用；加味芍药汤[24]理气活血，调经解毒止痛，尤善治结肠炎黏液脓血便症状；药毒与癌毒相合，久病伤正，导致气血不足、脾肾亏虚而疲乏，芪归补血糖浆[26]补气养血，对于疲乏患者的恢复效果显著。
2.3 扶正解毒化瘀法增强免疫治疗的效果
与西药特异性针对某一分子靶点不同，中医药靶点广、机制多，在调节免疫微环境、对免疫治疗增敏方面也具有突出优势。目前，桂枝茯苓丸和参芪扶正注射液已经在临床研究中被证实对PD-1/PD-L1抑制剂有增效作用，可以提高客观缓解率和疾病控制率，延长中位无进展生存期，详见表2。此外，肿瘤发生发展的过程中会产生诸多病理产物，如瘀血、痰火、湿毒等，与药毒共同侵袭人体正气，降低免疫水平，消除上述病理产物有助于提高免疫治疗的效果：桂枝茯苓丸[27]尤善于治妇人肝经血瘀癥聚，行气活血，化瘀消癥；参芪扶正注射液[28]善补脾肺之气以扶正，但少数患者使用后可能出现低热、嗜睡等症状，对本品过敏者也应慎用。
表 2 中医药增强免疫治疗疗效成果汇总Table 2 Efficacy of traditional Chinese medicine in enhancing effect of immunotherapyTCM Treatment duration Study type Study sample Study results Guizhi Guling pill[27] Three months Randomized controlled
clinical
studySixty patients with advanced ovarian cancer The objective response rate and disease control rate in the treatment group were 33.33% and 60.00%, respectively, both of which were significantly higher than those in the control group at 10.00% and 33.33%, respectively (P<0.05). Shenqi Fuzheng injection[28] Each 21-day period constitutes four treatment cycles Randomized controlled
clinical
study65 cases of advanced non-small cell lung cancer with negative driver genes The median progression-free survival time in the experimental group was significantly better than that in the control group (6.30 months vs. 5.54 months, P=0.043). 3 扶正解毒化瘀法的“减毒增效”机制
3.1 “减毒”机制
ICIs通过阻断PD-1/PD-L1或CTLA-4等免疫检查点，可能过度激活免疫系统，导致免疫细胞错误地攻击正常组织，使机体发生免疫相关不良事件。CAR-T细胞疗法，可能导致大量细胞因子的快速释放，引起高热、低血压、呼吸困难等严重症状。免疫治疗相关不良反应中皮疹和皮肤瘙痒往往最先出现，而腹泻及结肠炎最常见，在过往的研究中，伊匹木单抗导致腹泻发生率达41.2%，皮疹发生率34%[29]。嗜酸性粒细胞、白细胞介素、白细胞介素10、IgE的升高可能引发免疫相关性皮肤不良反应[30]，彭艳梅等[31]基于网络药理学分析发现，中药外用制剂止痒平肤液主要通过降低IL-6相关的炎性信号通路治疗皮疹和皮肤瘙痒。痛泻要方颗粒可以通过抑制促肾上腺皮质激素释放激素受体1表达减少肥大细胞的数量、调控肠道免疫、治疗免疫治疗造成肠道高敏环境引发的腹泻[32]。
目前针对中药对免疫治疗“减毒”的分子机制研究报道较少，后续本课题组将持续跟进。
3.2 “增效”机制
抑制肿瘤细胞PD-L1表达，或抑制细胞毒性T细胞表面PD-1的表达是抑制细胞毒性T细胞功能耗竭的重要机制，细胞毒性T细胞是杀伤肿瘤最主要的免疫细胞类型，也是人体正气的物质基础之一，恢复人体正气以解毒。而抑制调节免疫抑制细胞浸润或功能也是中药及提取物扶正以解癌毒的重要策略。
3.2.1 下调肿瘤细胞PD-L1的表达以增强细胞毒性T细胞的肿瘤杀伤作用
乏氧诱导因子-1α（Hypoxia inducible factor-1, HIF-1α）可以直接结合到PD-L1基因的启动子区域，促进其转录。姜黄素和人参二醇等单体成分可以通过PI3K/Akt/mTOR和MAPK信号通路抑制HIF-1α蛋白合成，进而抑制PD-L1水平。β-榄香烯是一种来源于姜黄的萜类化合物，可以特异性调节TE-1和KYSE-150等食管癌细胞中的Akt信号以抑制PD-L1的表达[33]。芹菜素是一种来源于洋甘菊、紫苏、马鞭草、车前子、络石藤等中药的黄酮类成分，可以通过抑制IFN-γ诱导的STAT1激活，以降低黑色素瘤细胞中PD-L1的表达水平[34]。人参皂苷Rg3可以通过下调EGFR信号转导来抑制PD-L1的糖基化，进而抑制其表达[35]。Teng等基于中医经典名方泽漆汤改编的活血益气方-2（Huoxue Yiqi Recipe-2, HYR-2）由丹参、人参、甘草等组成，可以通过上调嗜黏蛋白阿克曼菌的水平来下调PD-L1表达，增强PD-L1抗体疗效[36]。
3.2.2 下调细胞毒性T细胞表面PD-1的表达来抑制其功能耗竭
桔梗皂苷D和桔梗皂苷D3通过减少肿瘤细胞中p-STAT3水平调节VEGF-A分泌来调节CD8+T细胞表面PD-1的表达[37]。黄芪四君子汤通过促进T细胞PD-1泛素化以抑制胃癌细胞的增殖[38]。益脾活血方可以通过抑制PD-1的表达以抑制肝癌微环境中细胞毒性T细胞功能的耗竭[39]。
3.2.3 调节免疫抑制细胞浸润或功能
Mao等发现具有温阳补血功效的阳和汤可以通过降低肿瘤微环境中组织中髓源性抑制细胞（Myeloid-derived suppressor cells, MDSCs）和调节性T细胞（Regulatory T cells, Tregs）的比例促进T细胞活化，从而促进机体免疫应答，抑制乳腺癌小鼠肿瘤的生长[40]；Treg细胞是一种具有免疫抑制作用的T细胞亚群，在活化状态下加速肿瘤的侵袭和转移过程。西黄丸能够通过抑制磷脂酰肌醇3-激酶/蛋白激酶B（Phosphoinositide 3-kinase/protein kinase B, PI3K/AKT）信号通路，减少肿瘤微环境中Treg的数量，抑制肿瘤的生长和转移[41]。
M2型巨噬细胞也是肿瘤微环境中一种重要的免疫抑制细胞类型。补肺汤出自《永类钤方》，由人参、黄芪、五味子、紫菀、桑白皮、熟地黄六种中药熬制而成，可以通过抑制IL-10和PD-L1的表达阻断肿瘤相关巨噬细胞与癌细胞之间联系[42]；网络药理学和实验证实HYR-2可以促进M2巨噬细胞向M1巨噬细胞的转化，以促进细胞毒性T细胞对肿瘤的杀伤作用[36]。
4 展望
“扶正解毒化瘀”理论是指导中医药对免疫治疗增效减毒的重要思想。该理论统筹兼顾了肿瘤患者的中医体质特点、病因病机和免疫治疗对人体内稳态的调节作用。未来可以在该思想引领下，深入总结免疫治疗前后患者中医证型变化规律，不断探索中医协同免疫治疗的创新制剂，基于多组学测序结果阐明创新中药的分子机制，为临床选择安全有效、靶点明确、机制清晰的中药提供帮助。
Competing interests: The authors declare that they have no competing interests.利益冲突声明：所有作者均声明不存在利益冲突。作者贡献：陈昱帆：思路设计、论文撰写李思聪、崔译元：文献调研、文章校对冯 利：思路设计、资金支持及论文审阅修改 -
表 1 免疫相关不良反应中医药研究成果汇总表
Table 1 Researches of traditional Chinese medicine on immunotherapy-related adverse reactions
Immune-related
adverse effectsTraditional Chinese medicine Treatment
durationStudy
typeStudy
sampleStudy results Skin toxicity Clearing heat and removing dampness formula[18] (Si-Miao-Yong-An decoction +coix seed) For external use, up to a maximum of one month Retrospective cohort study 30 patients with grade 2-3 immune-related rash Among the patients, 13 who previously failed corticosteroid treatment experienced relief of pain symptoms associated with rashes after using the Clearing heat and removing dampness formula, with an overall effective rate of 70%. In all the patients, including those who had not previously received corticosteroid treatment, the median time for rashes to recover to grade 1 was 8 days, with a total effective rate of 80%. Nourishing yin and eliminating rash formula[19] Oral administration for two weeks Retrospective Cohort Study 25 patients with immune-related cutaneous adverse reactions Compared with no intervention and the use of hormone therapy, the combined treatment of Yin-nourishing and rash-reducing formula significantly alleviated the severity of rashes and feverish sensation in five centers and accelerated the rate of rash resolution. Jiedu Qingzhen formula[20] Continuous medication for
21 daysRandomized controlled
clinical trial72 patients with malignant tumors complicated with wind-heat sores treated with PD-1 inhibitors Compared with the management plan for immune-related skin adverse reactions recommended by the CSCO guidelines, the Jiedu Qingzhen formula significantly improved the grading of wind-heat sores, TCM syndromes, itching grading, KPS scores, and DLQI scores. Diarrhea Modified Sheng-Yang-Yi-Wei powder[21] / Randomized controlled
clinical trial60 patients with immune-related diarrhea due to malignant tumors of spleen yang deficiency syndrome at grades 2-3 Compared with those treated solely with Western medicine (toripalimab，, sintilimab, and camrelizumab), the patients who additionally received the modified Sheng-Yang-Yi-Wei powder treatment showed significant improvements in TCM syndrome scores (P<0.05) and a notable increase in KPS scores. Modified Chaihu Guizhi decoction[22] Continuous medication for
21 daysRandomized controlled
clinical trial92 cancer patients (including various types of cancer such as gallbladder cancer, lung cancer, and liver cancer) Compared with those under treatment plans that use only immunosuppressants, such as PD-1/PD-L1 inhibitors, the patients who additionally received modified Chaihu Guizhi decoction showed reduced incidence of colitis by 28% and improved diarrhea associated with PD-1 monoclonal antibody therapy. Colitis Wumei Pills[23] / Randomized controlled experiment
in ratsForty rats were randomly divided into five groups, with eight rats in each group Compared with that in the positive control group, the serum IL-1β expression was increased in the low- and high-dose Wumei Pill groups (P<0.05). The colonic IL-1β expression was decreased in both groups (P<0.05), indicating that Wumei Pill can ameliorate the pathological damage of immune colitis. Supplemented Shaoyao Decoction[24] For acute diarrhea, take medication continuously for 5 days; for chronic diarrhea, maintain treatment after the effect is shown. Randomized controlled
clinical trial80 patients with intestinal damp-heat type who developed colitis after immunotherapy Compared with loperamide alone, its combination with Shaoyao Decoction showed superior efficacy in improving the symptoms of acute and chronic diarrhea, abdominal pain, anal burning, and bitter taste in the mouth of patients with immune-related colitis. Hepatitis Ginsenoside Rd[25] / Cell experiments+
mouse experiments32 C57BL/6 mice were randomly divided into four groups, with eight mice in each group Ginsenoside Rd exerts a protective effect against immune hepatitis in mice by inhibiting the cGAS/STING/NLRP3 inflammasome signaling pathway. Cancer-Related Fatigue Qigui Buxue Syrup[26] A treatment cycle lasts for 21 days, with two cycles of treatment Randomized controlled clinical trial Fifty patients were enrolled and randomly divided into two groups Compared with the monotherapy of sintilimab, the combined treatment with Qigui Buxue Syrup can significantly improve the multidimensional fatigue status, TCM symptoms, and physical condition in patients with qi deficiency type advanced nonsmall cell lung cancer (NSCLC) after immunotherapy. It also enhances the efficacy of immunotherapy with a high safety profile. 
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表 2 中医药增强免疫治疗疗效成果汇总
Table 2 Efficacy of traditional Chinese medicine in enhancing effect of immunotherapy
TCM Treatment duration Study type Study sample Study results Guizhi Guling pill[27] Three months Randomized controlled
clinical
studySixty patients with advanced ovarian cancer The objective response rate and disease control rate in the treatment group were 33.33% and 60.00%, respectively, both of which were significantly higher than those in the control group at 10.00% and 33.33%, respectively (P<0.05). Shenqi Fuzheng injection[28] Each 21-day period constitutes four treatment cycles Randomized controlled
clinical
study65 cases of advanced non-small cell lung cancer with negative driver genes The median progression-free survival time in the experimental group was significantly better than that in the control group (6.30 months vs. 5.54 months, P=0.043).
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