肿瘤相关巨噬细胞:膀胱癌治疗靶点的前沿探索与研究新动态
Tumor-Associated Macrophages: Frontier Exploration and New Research Trends of Bladder Cancer Therapy Targets
DOI: 10.12677/acm.2025.1561804, PDF, HTML, XML,   
作者: 刘振华*, 郝亮亮, 赵家伟, 武超越, 马锦容, 胡耀强:延安大学延安医学院,陕西 延安;靳永胜#:延安大学附属医院泌尿外科,陕西 延安
关键词: 膀胱癌肿瘤微环境肿瘤相关巨噬细胞靶向治疗Bladder Cancer Tumor Microenvironment Tumor-Associated Macrophages Targeted Therapy
摘要: 膀胱癌是泌尿系统中最常见的恶性肿瘤之一,尽管现有的治疗手段包括手术、化疗和免疫疗法等,但晚期膀胱癌患者的总体生存率仍然较低。近年来,肿瘤微环境成为研究热点,尤其是肿瘤相关巨噬细胞在膀胱癌进展中的作用。肿瘤相关巨噬细胞在肿瘤微环境中通过促进肿瘤生长、转移和免疫逃逸,显著影响膀胱癌的预后。本文综述了肿瘤相关巨噬细胞的来源、极化及其对膀胱癌的影响,重点探讨了肿瘤相关巨噬细胞作为抗肿瘤免疫治疗靶点的潜力。未来的研究应进一步探索肿瘤相关巨噬细胞在膀胱癌中的具体机制,并开发更有效的靶向治疗方案,以改善患者的预后和生活质量。
Abstract: Bladder cancer is one of the most common malignant tumors in the urinary system. Although existing treatment methods include surgery, chemotherapy, and immunotherapy, the overall survival rate of patients with advanced bladder cancer remains low. In recent years, the tumor microenvironment has become a research hotspot, particularly the role of tumor-associated macrophages in the progression of bladder cancer. Tumor-associated macrophages significantly affect the prognosis of bladder cancer by promoting tumor growth, metastasis, and immune escape within the tumor microenvironment. This article reviews the origin, polarization of tumor-associated macrophages, and their impacts on bladder cancer, with a focus on discussing the potential of tumor-associated macrophages as targets for anti-tumor immunotherapy. Future research should further explore the specific mechanisms of tumor-associated macrophages in bladder cancer and develop more effective targeted therapy regimens to improve patients’ prognosis and quality of life.
文章引用:刘振华, 郝亮亮, 赵家伟, 武超越, 马锦容, 胡耀强, 靳永胜. 肿瘤相关巨噬细胞:膀胱癌治疗靶点的前沿探索与研究新动态[J]. 临床医学进展, 2025, 15(6): 899-906. https://doi.org/10.12677/acm.2025.1561804

1. 引言

膀胱癌(bladder cancer, BC)是泌尿系统中最常见的恶性肿瘤之一,具有高发病率、高复发率、易进展等特点。2020年,全球有573,278人新诊断出BC,根据世界卫生组织的预测,到2040年,这一数字预计将翻一番[1]。尿路上皮癌是BC最常见的类型,目前,大约75%的患者为非肌层浸润性膀胱癌(non-muscle invasive bladder cancer, NMIBC),25%为肌层浸润性膀胱癌(muscle invasive bladder cancer, MIBC)或转移性疾病。5年内,50%至70%的NMIBC会复发,10%至30%会进展为MIBC或转移性疾病[2]。临床上BC的主要治疗方式尽管有化疗、免疫疗法和手术等多种治疗方法,但晚期BC患者的总体生存率仍然很低,治疗效果不理想,为了提升疗效并改善患者预后状况,研究者们已将关注点聚焦于肿瘤微环境(tumor microenvironment, TME)。

TME由免疫细胞、基质细胞、细胞外基质(extracellular matrix, ECM)和信号分子等构成[3],肿瘤相关巨噬细胞(tumor-associated macrophages, TAM)在TME中扮演关键角色,参与肿瘤生长、转移和免疫逃逸等过程,其存在通常与实体瘤的不良预后相关[4]。近年来,随着对TAM研究的深入,TAM作为BC的潜在治疗靶点备受关注,尽管已有许多研究者对TAM在BC中的靶向治疗进行了探究,但关于免疫疗法联合TAM靶向治疗及其相关纳米技术的梳理仍较为匮乏。本综述旨在梳理TAM的来源、极化以及对BC的影响,重点探讨TAM作为抗肿瘤免疫治疗靶点在BC中的应用进展。

2. 肿瘤相关巨噬细胞的来源与极化

2.1. 来源

TME包括先天性和适应性免疫细胞,例如实体瘤中的T细胞、树突状细胞和巨噬细胞等。巨噬细胞大致分为三种群体,包括来源于单核细胞的TAM、组织驻留巨噬细胞(tissue-resident macrophages, TRM)和髓系抑制性细胞(myeloid-derived suppressor cells, MDSCs) [5]。TAM是TME中含量最丰富的肿瘤浸润免疫细胞之一,TAM起源于从骨髓中释放并被肿瘤分泌的趋化因子招募的单核细胞,或从TRM分化而来[6]。TAM的定义不仅限于识别浸润肿瘤的骨髓源性巨噬细胞,而应扩展到在TME中发挥作用的所有巨噬细胞,包括TRM。TAM的溯源多基于动物模型,故其在人类肿瘤中的情况仍不明晰,需更多证据阐明,以深入理解TAM在人类癌症进程中的意义与机制。

2.2. 极化

巨噬细胞具有高度可塑性,能依据微环境调整功能状态,主要分化为经典激活途径的M1型巨噬细胞和替代激活途径的M2型巨噬细胞两种截然不同的表型[7]。在干扰素-γ (IFN-γ)、肿瘤坏死因子-α (TNF-α)或脂多糖(LPS)等细胞因子刺激下,巨噬细胞极化为M1型[8],M1型巨噬细胞可激发免疫激活相关的促炎反应,抑制肿瘤生长,其重要特征是表达诱导型一氧化氮合酶(iNOS)、活性氧(ROS)和白介素-12 (IL-12)等[9]。而在IL-4、IL-10和IL-13等细胞因子刺激下,巨噬细胞极化为M2型,主要发挥免疫抑制与促肿瘤作用[10],与体内IL-10、IL-1β、血管内皮生长因子(VEGF)和基质金属蛋白酶(natrix netalloproteinases, MMPs)的高表达有关[11]。值得一提的是,M2型巨噬细胞还能进一步细分为M2a、M2b、M2c以及M2d [7] [12]

3. 肿瘤相关巨噬细胞对膀胱癌的影响

3.1. 促进膀胱癌生长与转移

TAM在BC的生长与转移进程中至关重要。在TME里,TAM通过多种途径助力肿瘤细胞生长。研究表明,E3泛素连接酶(SPOP)下调与肿瘤进展、TAM浸润正相关,肿瘤细胞与TAM相互作用依赖SPOP缺乏,当SPOP缺乏时,增加了STAT3蛋白的稳定性,提高了趋化因子配体2 (CCL2)的分泌,从而诱导了巨噬细胞的趋化性和M2型极化,最终推动了BC的进展。针对这种串扰可能为患有SPOP缺陷的BC患者提供一种有前途的治疗策略[13]。此外,M2型巨噬细胞相关特征(MMRS)中的CLDN6,能独立预测较差预后,通过影响免疫浸润和M2型极化促进BC生长,是BC预后的独立风险因素[14]

TAM还通过多种机制推动BC的侵袭与转移,如上皮–间质转化(epithelial-mesenchymal transition, EMT)、ECM重塑、血管以及淋巴管的形成等。TAM可分泌多种蛋白水解酶,包括MMPs、组织蛋白酶和丝氨酸蛋白酶,以降解细胞外基质(ECM),从而促进肿瘤细胞的迁移和侵袭[15]。MMPs是与肿瘤发生相关的蛋白酶家族,通过降解细胞外基质促进肿瘤的迁移。小鼠BC模型研究发现:磷脂酶D1 (PLD1)通过NF-κB信号通路调控MMP-13的表达,从而促进了BC的肿瘤侵袭[16]。此外,EMT在肿瘤进展与转移过程中作用关键,它通过使极化的上皮细胞转化为间质细胞,从而使肿瘤细胞具有侵袭和转移的能力。研究表明,TAM衍生的外泌体长链非编码RNA (lncRNA) HISLA在BC进展中至关重要,其衍生外泌体增强BC迁移和侵袭能力,沉默lncRNA HISLA可抑制相关过程,表明其能促进BC的EMT和转移[17]

3.2. 参与膀胱癌的免疫逃逸

先天性与适应性免疫细胞的相互作用在抗肿瘤免疫反应中至关重要,但TME可能转变为免疫抑制微环境,TAM在其中起关键作用。研究发现,分泌IL-10的TAM在MIBC中呈现出一种类似于M2型TAM的免疫抑制表型,其与以CD8+ T细胞耗竭、未成熟NK细胞和免疫检查点表达增加为特征的免疫逃逸肿瘤微环境相关,其会浸润TME并抑制免疫反应[18]。M2型TAM也可分泌转化生长因子-β (TGF-β)并提高BC糖酵解水平,通过丙酮酸激酶同工酶M2 (PKM2)在细胞程序性死亡–配体1 (programmed cell death ligand 1, PD-L1)介导的免疫逃逸中发挥重要作用[19]。此外,CD276通过增强TAM的胞葬作用,调控免疫细胞浸润,促进了BC的免疫逃逸。该研究揭示了CD276激活了溶酶体信号通路和转录因子JUN,以调节AXL和MerTK的表达,从而促进TAM的胞葬作用。因此CD276可以作为BC潜在免疫治疗靶点[20]。此外,一项国内关于TAM影响肝癌免疫逃逸的研究也进一步表明,TAM在肿瘤免疫抑制微环境中的关键作用。发现在p53失活的肝癌中,癌症干细胞(CSCs)会过度分泌IL-34,通过IL-34-CD36信号轴调控巨噬细胞的脂肪酸代谢过程,使得TAM向M2型极化,可抑制CD8+ T细胞介导的抗肿瘤免疫,从而促进免疫逃逸。揭示了p53调节TME的潜在机制,并为p53失活的癌症免疫疗法提供了潜在靶点[21]。深入探索TAM参与免疫逃逸机制,有助于优化癌症免疫治疗手段,以TAM为潜在靶点,也为BC免疫治疗开辟新方向。

4. 肿瘤相关巨噬细胞作为膀胱癌治疗的潜在靶点

手术和放化疗是BC的主要治疗策略,但手术风险大、化疗毒性大、术后复发率高,这些都阻碍了BC的治疗。多项研究表明,M2型TAM在BC中浸润增加,与患者的生存期缩短和不良预后相关[22]-[24]。因此,靶向TAM成为新兴的治疗策略,主要包括耗竭TAM、减少单核细胞的募集、TAM的重编程、免疫疗法联合靶向TAM以及相关纳米技术。

4.1. 耗竭肿瘤相关巨噬细胞

耗竭TME中的TAM,能够逆转免疫抑制微环境,实现癌症治疗。双膦酸盐类药物,如氯膦酸盐、唑来膦酸盐等,具有耗竭TAM的作用。有研究报道了一种基于双膦酸钙–聚乙二醇(CaBP-PEG)纳米颗粒诱导TAM耗竭后,可抑制血管生成,促使肿瘤血管结构正常化[25]。双膦酸盐在抑制肿瘤生长方面展现出了出色的协同治疗效果。此外,发现唑来膦酸(zoledernic acid, ZA)能被TAM吞噬,诱导其凋亡并向M1表型复极化[26]。此外,集落刺激因子1 (CSF1)及其受体CSF1R对巨噬细胞的存活、增殖和分化至关重要[27]。巨噬细胞依赖CSF1/CSF1R信号转导,使得CSF1R成为耗竭TAM的靶点,目前,针对CSF1R信号的多种抗体与小分子已被广泛研究。例如:培西达替尼(pexidartinib, PLX)以阻断CSF1R,从而耗竭TAM,重塑TME,促进T细胞向肿瘤组织的浸润,进而发挥抗肿瘤作用[28]

4.2. 减少单核细胞的募集

减少单核细胞的募集主要是抑制趋化因子与受体的相互作用,阻止单核细胞向TME迁移。CCL2在巨噬细胞募集中发挥着重要作用,并参与肿瘤细胞增殖和癌症转移[29]。小鼠实验表明,阻断CCL2-CCR2轴可阻碍单核细胞的募集,从而增强CD8+ T细胞在TME中的抗肿瘤作用[30]。此外,CCR4阳性调节性T细胞(Tregs)也可作为CCL2的受体,经CCL2-CCR4轴与M2型TAM形成正反馈环,被募集到TME中诱导肿瘤细胞转移。而CCR4拮抗剂C-021可抑制CCL2-CCR4激活,逆转CCR4+ Tregs浸润,降低肿瘤转移发生率[31]。研究发现CXCL12在BC中过度表达,与多种免疫细胞浸润相关,受SPI1调控影响TAM募集,为BC的研究提供了潜在的治疗靶点[32]。鉴于当前策略未充分考虑TAM在TME中的积极作用,单纯减少单核细胞的募集以及耗竭TAM这一策略存在固有局限。展望未来,可能更优选针对TAM的重编程策略,以保留潜在有益的TAM,为BC治疗开拓新方向。

4.3. 肿瘤相关巨噬细胞的重编程

重编程TAM是将促肿瘤的M2型TAM转变为抗肿瘤的M1型TAM,或者改变TAM的功能状态,使其从支持肿瘤生长转变为抑制肿瘤生长的过程。TME中的谷氨酰胺代谢对于抗肿瘤免疫起着至关重要的调节作用。一项报道表明,谷氨酰胺拮抗剂前药JHU083能通过重编程免疫抑制型TAM,抑制BC生长,也可改变TAM的功能,如对肿瘤细胞吞噬能力的增强以及促血管生成能力的减弱,从而促进抗肿瘤免疫反应[33],为富含免疫抑制型TAM的肿瘤类型提供有效的治疗益处。FGFR3突变在BC患者中较为常见。突变的FGFR3诱导BC中丝氨酸合成增加,激活了巨噬细胞中的PI3K/Akt通路,使其转变为免疫惰性表型,从而产生了免疫抑制型TME。用PI3K抑制剂duvelisib靶向突变的FGFR3肿瘤中的PI3K,通过逆转巨噬细胞表型获得了很好的疗效,并且与erdafitinib联合具有更强的抗肿瘤活性[34]。erdafitinib是一种泛FGFR抑制剂,是目前FDA批准用于治疗晚期或转移性尿路上皮癌的唯一酪氨酸激酶抑制剂[35]。此外,IFN对激活有效的免疫反应至关重要,研究表明,IFN-λ3通过重编程巨噬细胞介导的吞噬作用,显著增加了细胞毒性CD8+ T细胞、Th1细胞和自然杀伤细胞的浸润,从而抑制BC的进展[36]。然而,在传统中药猪苓中也发现具有重编程TAM的作用,从猪苓中分离出了高纯度的均一猪苓多糖(HPP),HPP促进了巨噬细胞中促炎因子(如IL-1β、TNF-α和iNOS)以及表面分子(如CD86、CD16、CD23和CD40)的表达,进而将巨噬细胞极化为M1型[37]。这一极化过程可通过NF-κB/NLRP3信号通路调节巨噬细胞的极化,从而改善TME,抑制了BC的增殖和进展[38],因此HPP可作为一种潜在的膀胱癌治疗药物。

4.4. 免疫疗法联合靶向肿瘤相关巨噬细胞

对于BC的免疫治疗,目前主要包括膀胱内灌注卡介苗(BCG)和免疫检查点抑制剂(ICI)。BCG免疫疗法仍是治疗NMIBC的黄金标准,但许多患者会复发并进展为MIBC,而后者对BCG具有耐药性。纳米颗粒与现有免疫疗法联合可增强疗效,工程化巨噬细胞在BC治疗中作为药物递送和免疫疗法的工具很有前景,研究者设计了一种纳米颗粒负载的巨噬细胞(MINS),将CpG连接的磁性纳米团簇(MNC)、吲哚菁绿(ICG)和尼日利亚霉素(NIG)结合在一起,并用硒–硒键修饰的二氧化硅进行封装,用于BC的治疗。由于BCG介导的肿瘤局部炎症,MINS@MΦ得以靶向积聚于肿瘤组织内,通过激光照射激活MINS@MΦ,释放Fe2+和CpG,促进TAM向M1型极化和分泌抗肿瘤细胞因子[39]。这种创新方法通过精确调节细胞因子,优化并增强了BCG免疫疗法的有效性,为BC治疗提供了有效的解决方案,同时避免了全身性炎症反应的发生。此外,在巨噬细胞中诱导训练免疫是一种有前景的癌症预防策略。利用巨噬细胞膜(M)伪装卡介苗(M@BCG),使其能够选择性靶向肿瘤并有效诱导TAM的训练免疫。通过Lewis肺癌的小鼠模型,我们发现巨噬细胞膜的引入增加了BCG在肺癌组织中的累积量,肿瘤靶向能力的增强,促使BCG对TAM训练免疫的效果得以提升,从而激活强烈的免疫反应[40]

近年来,ICI在BC治疗中取得了显著进展,但应答率仍然较低,大约80%的晚期BC患者对此治疗无反应[41],只有部分患者能从中受益,原因可能是肿瘤的高度异质性和TME的改变,因此可通过联合靶向TAM,提升ICI的疗效。研究发现,在相当一部分人类MIBC标本中,树突状细胞特异性C型凝集素(DC-SIGN)的TAM含量丰富,其高水平与MIBC的预后不良和对辅助化疗无反应有关。RNA-seq分析显示,在DC-SIGN+ TAM中多表达为M2型,高水平的DC-SIGN+ TAM的浸润与TME密切相关,这些DC-SIGN+ TAM富含抗炎细胞因子,并且与CD8+ T细胞的耐受性相关,抑制DC-SIGN+ TAM功能可以增强PD-1抑制剂pembrolizumab对MIBC的免疫反应[42]。此外,还发现了烟酰胺N-甲基转移酶(NNMT)在癌症相关成纤维细胞(CAF)中的高表达与BC患者对PD-L1阻断免疫疗法无反应显著相关。NNMT+ CAFs通过对血清淀粉样蛋白A (SAA)进行表观遗传学重编程来募集TAM,从而驱动肿瘤细胞增殖。在小鼠BC模型中,使用抑制剂5-Amino-1-methylquinolinium iodide靶向NNMT能显著抑制肿瘤生长,提高抗PD-L1免疫疗法在BC中的疗效[43]

4.5. 相关纳米技术

纳米技术在BC治疗中潜力巨大,纳米颗粒可精确递送药物至肿瘤部位,减少全身毒性,并通过多模式治疗增强疗效。例如,纳米颗粒可靶向TAM,调控TME中的细胞因子和信号通路,促进TAM向抗肿瘤表型极化,或与现有免疫疗法联合使用,增强局部免疫反应。研究人员首次提出经膀胱内递送磁性纳米粒子的温和磁热疗(MHT)治疗BC的新方法,开发并修饰核壳Zn-CoFe2O4@Zn-MnFe2O4(MNP)纳米粒子,克服了传统静脉给药存在的局限。在43~44℃下,该方法能够有效抑制肿瘤增殖与生长,逆转BC的免疫抑制环境,激活免疫反应,显著减少肿瘤复发,具备广阔的临床应用前景[44]。此外,X射线光动力疗法(XPDT)作为一种新兴的肿瘤治疗方法,却因治疗药物递送不足和TME中的免疫抑制因素受到限制。为此,研究人员开发出响应X射线的铁–甘油醇壳聚糖–聚吡咯纳米酶(GCS-I-PPy NZs),这种纳米酶能够激活M1型巨噬细胞。经X射线照射后,它们在TME中产生活性氧(ROS),显著增强XPDT的治疗效果,同时促进T细胞的肿瘤浸润[45]

5. 展望

随着对TME和TAM在BC进展中作用的深入理解,免疫治疗联合靶向治疗和纳米技术的应用前景日益广阔。目前针对TAM的治疗策略仍处于早期阶段,未来的研究应聚焦于通过免疫治疗联合靶向治疗的策略,提升治疗效果。ICI在BC治疗中已取得进展,但其应答率有限,未来可通过靶向TAM来增强ICI疗效。此外,未来需进一步探索纳米颗粒的生物学效应、安全性及临床转化潜力,开发更精准的靶向药物和个性化治疗方案,为BC患者带来更好的预后和生活质量。

NOTES

*第一作者。

#通讯作者。

参考文献

[1] Dyrskjøt, L., Hansel, D.E., Efstathiou, J.A., Knowles, M.A., Galsky, M.D., Teoh, J., et al. (2023) Bladder Cancer. Nature Reviews Disease Primers, 9, Article No. 58.
https://doi.org/10.1038/s41572-023-00468-9
[2] Kamat, A.M., Hahn, N.M., Efstathiou, J.A., Lerner, S.P., Malmström, P., Choi, W., et al. (2016) Bladder Cancer. The Lancet, 388, 2796-2810.
https://doi.org/10.1016/s0140-6736(16)30512-8
[3] Baghban, R., Roshangar, L., Jahanban-Esfahlan, R., Seidi, K., Ebrahimi-Kalan, A., Jaymand, M., et al. (2020) Tumor Microenvironment Complexity and Therapeutic Implications at a Glance. Cell Communication and Signaling, 18, Article No. 59.
https://doi.org/10.1186/s12964-020-0530-4
[4] DeNardo, D.G. and Ruffell, B. (2019) Macrophages as Regulators of Tumour Immunity and Immunotherapy. Nature Reviews Immunology, 19, 369-382.
https://doi.org/10.1038/s41577-019-0127-6
[5] Chen, Y., Song, Y., Du, W., Gong, L., Chang, H. and Zou, Z. (2019) Tumor-Associated Macrophages: An Accomplice in Solid Tumor Progression. Journal of Biomedical Science, 26, Article No. 78.
https://doi.org/10.1186/s12929-019-0568-z
[6] Zhao, L., Wang, Z., Tan, Y., Ma, J., Huang, W., Zhang, X., et al. (2024) Il-17A/CEBPβ/OPN/LYVE-1 Axis Inhibits Anti-Tumor Immunity by Promoting Tumor-Associated Tissue-Resident Macrophages. Cell Reports, 43, Article 115039.
https://doi.org/10.1016/j.celrep.2024.115039
[7] Pan, Y., Yu, Y., Wang, X. and Zhang, T. (2020) Tumor-Associated Macrophages in Tumor Immunity. Frontiers in Immunology, 11, Article 583084.
https://doi.org/10.3389/fimmu.2020.583084
[8] O’Neill, L.A.J., Kishton, R.J. and Rathmell, J. (2016) A Guide to Immunometabolism for Immunologists. Nature Reviews Immunology, 16, 553-565.
https://doi.org/10.1038/nri.2016.70
[9] Zhu, S., Yi, M., Wu, Y., Dong, B. and Wu, K. (2021) Roles of Tumor-Associated Macrophages in Tumor Progression: Implications on Therapeutic Strategies. Experimental Hematology & Oncology, 10, Article No. 60.
https://doi.org/10.1186/s40164-021-00252-z
[10] Murray, P.J. (2017) Macrophage Polarization. Annual Review of Physiology, 79, 541-566.
https://doi.org/10.1146/annurev-physiol-022516-034339
[11] Annamalai, R.T., Turner, P.A., Carson, W.F., Levi, B., Kunkel, S. and Stegemann, J.P. (2018) Harnessing Macrophage-Mediated Degradation of Gelatin Microspheres for Spatiotemporal Control of BMP2 Release. Biomaterials, 161, 216-227.
https://doi.org/10.1016/j.biomaterials.2018.01.040
[12] Chanmee, T., Ontong, P., Konno, K. and Itano, N. (2014) Tumor-Associated Macrophages as Major Players in the Tumor Microenvironment. Cancers, 6, 1670-1690.
https://doi.org/10.3390/cancers6031670
[13] Li, M., Cui, Y., Qi, Q., Liu, J., Li, J., Huang, G., et al. (2024) SPOP Downregulation Promotes Bladder Cancer Progression Based on Cancer Cell-Macrophage Crosstalk via STAT3/CCL2/IL-6 Axis and Is Regulated by Vezf1. Theranostics, 14, 6543-6559.
https://doi.org/10.7150/thno.101575
[14] Qi, D., Lu, Y., Qu, H., Dong, Y., Jin, Q., Sun, M., et al. (2024) Independent Prognostic Value of CLDN6 in Bladder Cancer Based on M2 Macrophages Related Signature. iScience, 27, Article 109138.
https://doi.org/10.1016/j.isci.2024.109138
[15] Kessenbrock, K., Plaks, V. and Werb, Z. (2010) Matrix Metalloproteinases: Regulators of the Tumor Microenvironment. Cell, 141, 52-67.
https://doi.org/10.1016/j.cell.2010.03.015
[16] Nagumo, Y., Kandori, S., Tanuma, K., Nitta, S., Chihara, I., Shiga, M., et al. (2021) PLD1 Promotes Tumor Invasion by Regulation of MMP-13 Expression via NF-κB Signaling in Bladder Cancer. Cancer Letters, 511, 15-25.
https://doi.org/10.1016/j.canlet.2021.04.014
[17] Guo, Y., Li, Z., Sun, W., Gao, W., Liang, Y., Mei, Z., et al. (2022) M2 Tumor Associate Macrophage-(TAM-) Derived LncRNA HISLA Promotes EMT Potential in Bladder Cancer. Journal of Oncology, 2022, Article 8268719.
https://doi.org/10.1155/2022/8268719
[18] Xu, Y., Zeng, H., Jin, K., Liu, Z., Zhu, Y., Xu, L., et al. (2022) Immunosuppressive Tumor-Associated Macrophages Expressing Interlukin-10 Conferred Poor Prognosis and Therapeutic Vulnerability in Patients with Muscle-Invasive Bladder Cancer. Journal for ImmunoTherapy of Cancer, 10, e003416.
https://doi.org/10.1136/jitc-2021-003416
[19] Yu, Y., Liang, Y., Xie, F., Zhang, Z., Zhang, P., Zhao, X., et al. (2024) Tumor-Associated Macrophage Enhances PD-L1-Mediated Immune Escape of Bladder Cancer through PKM2 Dimer-STAT3 Complex Nuclear Translocation. Cancer Letters, 593, Article 216964.
https://doi.org/10.1016/j.canlet.2024.216964
[20] Cheng, M., Chen, S., Li, K., Wang, G., Xiong, G., Ling, R., et al. (2024) CD276-Dependent Efferocytosis by Tumor-Associated Macrophages Promotes Immune Evasion in Bladder Cancer. Nature Communications, 15, Article No. 2818.
https://doi.org/10.1038/s41467-024-46735-5
[21] Nian, Z., Dou, Y., Shen, Y., Liu, J., Du, X., Jiang, Y., et al. (2024) Interleukin-34-Orchestrated Tumor-Associated Macrophage Reprogramming Is Required for Tumor Immune Escape Driven by P53 Inactivation. Immunity, 57, 2344-2361.E7.
https://doi.org/10.1016/j.immuni.2024.08.015
[22] Koll, F.J., Banek, S., Kluth, L., Köllermann, J., Bankov, K., Chun, F.K.-H., et al. (2023) Tumor-Associated Macrophages and Tregs Influence and Represent Immune Cell Infiltration of Muscle-Invasive Bladder Cancer and Predict Prognosis. Journal of Translational Medicine, 21, Article No. 124.
https://doi.org/10.1186/s12967-023-03949-3
[23] Sun, M., Zeng, H., Jin, K., Liu, Z., Hu, B., Liu, C., et al. (2022) Infiltration and Polarization of Tumor-Associated Macrophages Predict Prognosis and Therapeutic Benefit in Muscle-Invasive Bladder Cancer. Cancer Immunology, Immunotherapy, 71, 1497-1506.
https://doi.org/10.1007/s00262-021-03098-w
[24] Qu, G., Liu, Z., Yang, G., Xu, Y., Xiang, M. and Tang, C. (2021) Development of a Prognostic Index and Screening of Prognosis Related Genes Based on an Immunogenomic Landscape Analysis of Bladder Cancer. Aging, 13, 12099-12112.
https://doi.org/10.18632/aging.202917
[25] Tian, L., Yi, X., Dong, Z., Xu, J., Liang, C., Chao, Y., et al. (2018) Calcium Bisphosphonate Nanoparticles with Chelator-Free Radiolabeling to Deplete Tumor-Associated Macrophages for Enhanced Cancer Radioisotope Therapy. ACS Nano, 12, 11541-11551.
https://doi.org/10.1021/acsnano.8b06699
[26] Coscia, M., Quaglino, E., Iezzi, M., Curcio, C., Pantaleoni, F., Riganti, C., et al. (2010) Zoledronic Acid Repolarizes Tumour-Associated Macrophages and Inhibits Mammary Carcinogenesis by Targeting the Mevalonate Pathway. Journal of Cellular and Molecular Medicine, 14, 2803-2815.
https://doi.org/10.1111/j.1582-4934.2009.00926.x
[27] del Mar Maldonado, M., Schlom, J. and Hamilton, D.H. (2023) Blockade of Tumor-Derived Colony-Stimulating Factor 1 (CSF1) Promotes an Immune-Permissive Tumor Microenvironment. Cancer Immunology, Immunotherapy, 72, 3349-3362.
https://doi.org/10.1007/s00262-023-03496-2
[28] Li, Z., Ding, Y., Liu, J., Wang, J., Mo, F., Wang, Y., et al. (2022) Depletion of Tumor Associated Macrophages Enhances Local and Systemic Platelet-Mediated Anti-PD-1 Delivery for Post-Surgery Tumor Recurrence Treatment. Nature Communications, 13, Article No. 1845.
https://doi.org/10.1038/s41467-022-29388-0
[29] Chen, C., He, W., Huang, J., Wang, B., Li, H., Cai, Q., et al. (2018) LNMAT1 Promotes Lymphatic Metastasis of Bladder Cancer via CCL2 Dependent Macrophage Recruitment. Nature Communications, 9, Article No. 3826.
https://doi.org/10.1038/s41467-018-06152-x
[30] Yang, H., Zhang, Q., Xu, M., Wang, L., Chen, X., Feng, Y., et al. (2020) CCL2-CCR2 Axis Recruits Tumor Associated Macrophages to Induce Immune Evasion through PD-1 Signaling in Esophageal Carcinogenesis. Molecular Cancer, 19, Article No. 41.
https://doi.org/10.1186/s12943-020-01165-x
[31] Chiang, Y., Lu, L., Tsai, C., Tsai, Y., Wang, C., Hsueh, F., et al. (2024) C-C Chemokine Receptor 4 (CCR4)-Positive Regulatory T Cells Interact with Tumor-Associated Macrophages to Facilitate Metastatic Potential after Radiation. European Journal of Cancer, 198, Article 113521.
https://doi.org/10.1016/j.ejca.2023.113521
[32] Lu, G. and Qiu, Y. (2023) Spi1-Mediated CXCL12 Expression in Bladder Cancer Affects the Recruitment of Tumor‐associated Macrophages. Molecular Carcinogenesis, 63, 448-460.
https://doi.org/10.1002/mc.23663
[33] Praharaj, M., Shen, F., Lee, A.J., Zhao, L., Nirschl, T.R., Theodros, D., et al. (2024) Metabolic Reprogramming of Tumor-Associated Macrophages Using Glutamine Antagonist JHU083 Drives Tumor Immunity in Myeloid-Rich Prostate and Bladder Cancers. Cancer Immunology Research, 12, 854-875.
https://doi.org/10.1158/2326-6066.cir-23-1105
[34] Ouyang, Y., Ou, Z., Zhong, W., Yang, J., Fu, S., Ouyang, N., et al. (2023) FGFR3 Alterations in Bladder Cancer Stimulate Serine Synthesis to Induce Immune-Inert Macrophages That Suppress T-Cell Recruitment and Activation. Cancer Research, 83, 4030-4046.
https://doi.org/10.1158/0008-5472.can-23-1065
[35] Loriot, Y., Matsubara, N., Park, S.H., Huddart, R.A., Burgess, E.F., Houede, N., et al. (2023) Erdafitinib or Chemotherapy in Advanced or Metastatic Urothelial Carcinoma. New England Journal of Medicine, 389, 1961-1971.
https://doi.org/10.1056/nejmoa2308849
[36] Wang, B., Zhou, B., Chen, J., Sun, X., Yang, W., Yang, T., et al. (2024) Type III Interferon Inhibits Bladder Cancer Progression by Reprogramming Macrophage-Mediated Phagocytosis and Orchestrating Effective Immune Responses. Journal for ImmunoTherapy of Cancer, 12, e007808.
https://doi.org/10.1136/jitc-2023-007808
[37] Jia, W., Luo, S., Lai, G., Li, S., Huo, S., Li, M., et al. (2021) Homogeneous Polyporus Polysaccharide Inhibits Bladder Cancer by Polarizing Macrophages to M1 Subtype in Tumor Microenvironment. BMC Complementary Medicine and Therapies, 21, Article No. 150.
https://doi.org/10.1186/s12906-021-03318-x
[38] Liu, C., He, D., Zhang, S., Chen, H., Zhao, J., Li, X., et al. (2022) Homogeneous Polyporus Polysaccharide Inhibit Bladder Cancer by Resetting Tumor-Associated Macrophages toward M1 through NF-κB/NLRP3 Signaling. Frontiers in Immunology, 13, Article 839460.
https://doi.org/10.3389/fimmu.2022.839460
[39] Guo, P., Dai, P., Yang, S., Wang, Z., Tong, Z., Hou, D., et al. (2023) Engineered Macrophages Tune Intratumoral Cytokines through Precisely Controlled Self-Pyroptosis to Enhance Bladder Cancer Immunotherapy. Small, 20, Article 2306699.
https://doi.org/10.1002/smll.202306699
[40] Zhang, L., Xiao, Z., Zhang, D., Yang, L., Yuan, Z., Wang, G., et al. (2024) Targeted Initiation of Trained Immunity in Tumor-Associated Macrophages with Membrane-Camouflaged Bacillus Calmette-Guérin for Lung Carcinoma Immunotherapy. ACS Nano, 18, 34219-34234.
https://doi.org/10.1021/acsnano.4c11658
[41] Xu, D., Wang, L., Wieczorek, K., Zhang, Y., Wang, Z., Wang, J., et al. (2022) Single-Cell Analyses of a Novel Mouse Urothelial Carcinoma Model Reveal a Role of Tumor-Associated Macrophages in Response to Anti-PD-1 Therapy. Cancers, 14, Article 2511.
https://doi.org/10.3390/cancers14102511
[42] Hu, B., Wang, Z., Zeng, H., Qi, Y., Chen, Y., Wang, T., et al. (2020) Blockade of DC-SIGN+ Tumor-Associated Macrophages Reactivates Antitumor Immunity and Improves Immunotherapy in Muscle-Invasive Bladder Cancer. Cancer Research, 80, 1707-1719.
https://doi.org/10.1158/0008-5472.can-19-2254
[43] Yang, M., Wang, B., Hou, W., Zeng, H., He, W., Zhang, X., et al. (2024) NAD+ Metabolism Enzyme NNMT in Cancer-Associated Fibroblasts Drives Tumor Progression and Resistance to Immunotherapy by Modulating Macrophages in Urothelial Bladder Cancer. Journal for ImmunoTherapy of Cancer, 12, e009281.
https://doi.org/10.1136/jitc-2024-009281
[44] Qi, F., Bao, Q., Hu, P., Guo, Y., Yan, Y., Yao, X., et al. (2024) Mild Magnetic Hyperthermia-Activated Immuno-Responses for Primary Bladder Cancer Therapy. Biomaterials, 307, Article 122514.
https://doi.org/10.1016/j.biomaterials.2024.122514
[45] Chuang, A.E.-Y., Tao, Y., Dong, S., Nguyen, H.T. and Liu, C. (2024) Polypyrrole/Iron-Glycol Chitosan Nanozymes Mediate M1 Macrophages to Enhance the X-Ray-Triggered Photodynamic Therapy for Bladder Cancer by Promoting Antitumor Immunity. International Journal of Biological Macromolecules, 280, Article 135608.
https://doi.org/10.1016/j.ijbiomac.2024.135608