癌(ai)癥遠(yuan)非單純的遺傳性疾病，而是(shi)一個(ge)動態(tai)演化的生態(tai)系(xi)統。在這個(ge)系(xi)統中，腫瘤細(xi)胞(bao)與非癌(ai)細(xi)胞(bao)（包括免疫細(xi)胞(bao)、基(ji)質(zhi)細(xi)胞(bao)、微生物群(qun)落）通過復雜的信號網(wang)絡、代謝互(hu)作和(he)空間(jian)競(jing)爭共同塑造了腫瘤微環境（TME），進(jin)而驅動癌(ai)癥的進(jin)展與治療抵(di)抗。

腫瘤(liu)(liu)微(wei)環(huan)境(jing)（TME）被認為(wei)是(shi)腫瘤(liu)(liu)發生(sheng)和(he)擴散(san)的重要部分。TME的復雜性是(shi)由于不受(shou)調節的癌細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)增(zeng)殖和(he)缺(que)陷的血管(guan)發育[1]。TME包(bao)括多種免疫(yi)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)、腫瘤(liu)(liu)相關成(cheng)纖維(wei)(wei)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)( CAFs )、內皮細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)和(he)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)外(wai)基質( ECM )等。這(zhe)些成(cheng)分可(ke)能因(yin)組織類型而(er)異(yi)，并隨著腫瘤(liu)(liu)的進展而(er)共同進化。正(zheng)常(chang)的組織微(wei)環(huan)境(jing)可(ke)以(yi)通過免疫(yi)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)、成(cheng)纖維(wei)(wei)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)和(he)細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)外(wai)基質的抑制功能來(lai)限制腫瘤(liu)(liu)的生(sheng)長。然而(er)，為(wei)了(le)癌癥的進展，它必(bi)須逃避這(zhe)些功能，并反過來(lai)影響TME中(zhong)的細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)成(cheng)為(wei)腫瘤(liu)(liu)促進細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)，從而(er)導致原發部位的增(zeng)殖、侵襲和(he)內侵增(zeng)加(jia)。TME的細(xi)(xi)(xi)胞(bao)(bao)(bao)(bao)和(he)因(yin)子(zi)在預備(bei)中(zhong)也起著至關重要的作(zuo)用。

圖1 原發(fa)性腫瘤進(jin)展(zhan)和轉移的微環境(jing)調控[2]

腫瘤免疫(yi)治療

將免(mian)(mian)疫(yi)系統(tong)作為(wei)治療(liao)(liao)(liao)(liao)腫(zhong)(zhong)(zhong)瘤(liu)(liu)性(xing)(xing)疾病的(de)(de)工具的(de)(de)想法(fa)起源于19世(shi)紀[3]。150年(nian)前，魏爾嘯在觀察(cha)腫(zhong)(zhong)(zhong)瘤(liu)(liu)中白細胞(bao)的(de)(de)流(liu)行情況(kuang)時(shi)首次提(ti)出了免(mian)(mian)疫(yi)功(gong)能與癌(ai)癥(zheng)之(zhi)間的(de)(de)關(guan)鍵關(guan)系[4]。2011年(nian)，ipilimumab (Yervoy)獲(huo)批上(shang)市，開啟(qi)了臨(lin)(lin)床療(liao)(liao)(liao)(liao)效持久的(de)(de)腫(zhong)(zhong)(zhong)瘤(liu)(liu)免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)新(xin)時(shi)代(dai)。癌(ai)癥(zheng)免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)通過(guo)延長快速致(zhi)命癌(ai)癥(zheng)患者的(de)(de)生(sheng)存期，現(xian)在已經徹底(di)改變了腫(zhong)(zhong)(zhong)瘤(liu)(liu)學領域。腫(zhong)(zhong)(zhong)瘤(liu)(liu)免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)是指外源干(gan)預機(ji)體(ti)免(mian)(mian)疫(yi)系統(tong)，重(zhong)新(xin)啟(qi)動并維持“腫(zhong)(zhong)(zhong)瘤(liu)(liu)-免(mian)(mian)疫(yi)”循環(huan)，恢復、提(ti)高(gao)機(ji)體(ti)的(de)(de)抗腫(zhong)(zhong)(zhong)瘤(liu)(liu)免(mian)(mian)疫(yi)反應，加(jia)強對腫(zhong)(zhong)(zhong)瘤(liu)(liu)細胞(bao)的(de)(de)識別(bie)和殺(sha)傷能力，從而達到控制甚至特異性(xing)(xing)清除腫(zhong)(zhong)(zhong)瘤(liu)(liu)的(de)(de)治療(liao)(liao)(liao)(liao)效果。相(xiang)較(jiao)于手術、放(fang)療(liao)(liao)(liao)(liao)和化(hua)療(liao)(liao)(liao)(liao)等傳統(tong)方法(fa)，免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)具有(you)特異性(xing)(xing)強，副作用相(xiang)對較(jiao)小的(de)(de)的(de)(de)優勢。目前臨(lin)(lin)床應用的(de)(de)腫(zhong)(zhong)(zhong)瘤(liu)(liu)免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)方法(fa)包括：免(mian)(mian)疫(yi)檢(jian)查點(dian)抑(yi)制劑(ji)、過(guo)繼(ji)性(xing)(xing)細胞(bao)免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)、癌(ai)癥(zheng)疫(yi)苗，以及一些新(xin)興免(mian)(mian)疫(yi)治療(liao)(liao)(liao)(liao)方法(fa)等。

免(mian)疫(yi)功(gong)能與(yu)腫瘤(liu)的免(mian)疫(yi)反應

NK細(xi)(xi)(xi)胞(bao)(bao)(bao)負責第一(yi)輪先天(tian)免(mian)疫(yi)反應(ying)(ying)，吞噬(shi)腫(zhong)(zhong)(zhong)瘤(liu)(liu)細(xi)(xi)(xi)胞(bao)(bao)(bao)。樹突狀細(xi)(xi)(xi)胞(bao)(bao)(bao)侵入腫(zhong)(zhong)(zhong)瘤(liu)(liu)，吞噬(shi)并(bing)將腫(zhong)(zhong)(zhong)瘤(liu)(liu)抗(kang)(kang)原呈遞(di)給各(ge)種類型T細(xi)(xi)(xi)胞(bao)(bao)(bao)( CD4+輔助性(xing)T細(xi)(xi)(xi)胞(bao)(bao)(bao)和(he)CD8+效(xiao)(xiao)應(ying)(ying)性(xing)T細(xi)(xi)(xi)胞(bao)(bao)(bao)，調(diao)節性(xing)T細(xi)(xi)(xi)胞(bao)(bao)(bao)( TReg)細(xi)(xi)(xi)胞(bao)(bao)(bao)、自然(ran)殺傷( NK )細(xi)(xi)(xi)胞(bao)(bao)(bao)），以(yi)(yi)便腫(zhong)(zhong)(zhong)瘤(liu)(liu)引(yin)流(liu)淋巴結中激活T細(xi)(xi)(xi)胞(bao)(bao)(bao)。活化的(de)CD4+和(he)CD8+效(xiao)(xiao)應(ying)(ying)T細(xi)(xi)(xi)胞(bao)(bao)(bao)和(he)NK細(xi)(xi)(xi)胞(bao)(bao)(bao)通(tong)過外(wai)周血返(fan)回到(dao)腫(zhong)(zhong)(zhong)瘤(liu)(liu)床，有助于(yu)基于(yu)腫(zhong)(zhong)(zhong)瘤(liu)(liu)-抗(kang)(kang)原啟動的(de)進一(yi)步腫(zhong)(zhong)(zhong)瘤(liu)(liu)消退。TReg細(xi)(xi)(xi)胞(bao)(bao)(bao)同樣可以(yi)(yi)返(fan)回腫(zhong)(zhong)(zhong)瘤(liu)(liu)并(bing)抑制(zhi)效(xiao)(xiao)應(ying)(ying)T細(xi)(xi)(xi)胞(bao)(bao)(bao)和(he)NK細(xi)(xi)(xi)胞(bao)(bao)(bao)的(de)殺傷效(xiao)(xiao)率，以(yi)(yi)防(fang)止明(ming)顯的(de)炎癥和(he)鄰(lin)近正常組(zu)織的(de)損傷。髓系來源的(de)抑制(zhi)性(xing)細(xi)(xi)(xi)胞(bao)(bao)(bao)( MDSCs )參與免(mian)疫(yi)抑制(zhi)調(diao)節，進一(yi)步參與這種調(diao)節，并(bing)可間接促進腫(zhong)(zhong)(zhong)瘤(liu)(liu)的(de)存活和(he)生長。B細(xi)(xi)(xi)胞(bao)(bao)(bao)產生針對(dui)腫(zhong)(zhong)(zhong)瘤(liu)(liu)抗(kang)(kang)原的(de)抗(kang)(kang)體，從而有助于(yu)腫(zhong)(zhong)(zhong)瘤(liu)(liu)的(de)根除。巨噬(shi)細(xi)(xi)(xi)胞(bao)(bao)(bao)分(fen)(fen)泌各(ge)種細(xi)(xi)(xi)胞(bao)(bao)(bao)因子，侵入并(bing)分(fen)(fen)化為腫(zhong)(zhong)(zhong)瘤(liu)(liu)抑制(zhi)（M1）和(he)腫(zhong)(zhong)(zhong)瘤(liu)(liu)促進（M2）譜系。成纖維細(xi)(xi)(xi)胞(bao)(bao)(bao)構建(jian)腫(zhong)(zhong)(zhong)瘤(liu)(liu)微環境，還可以(yi)(yi)分(fen)(fen)泌各(ge)種免(mian)疫(yi)抑制(zhi)劑，對(dui)抗(kang)(kang)免(mian)疫(yi)部(bu)隊。

圖2 免疫功能與腫瘤的免疫反應[5]

派森諾腫瘤(liu)免疫(yi)治療研究案(an)例

《Cell Metabolism》 ：微生物代(dai)謝物氧化三(san)甲(jia)胺(an)促(cu)進三(san)陰性(xing)乳腺癌的抗腫瘤免疫

英文題目：The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer.

期刊名(ming)：Cell Metabolism

影響因子(zi)：27.7

組學技術：16S V3V4多樣性組成譜、TMAO靶向代謝

主要研究結(jie)果：對三(san)陰(yin)性乳腺癌（TNBC）隊(dui)列（n=360）的(de)(de)(de)(de)(de)多(duo)組學分析(xi)發現，免(mian)(mian)(mian)疫(yi)調節(jie)亞型(xing)（腫(zhong)瘤微環境免(mian)(mian)(mian)疫(yi)活(huo)化）患者的(de)(de)(de)(de)(de)腫(zhong)瘤組織中，Clostridiales目的(de)(de)(de)(de)(de)多(duo)個(ge)菌(jun)屬及相關代謝產(chan)物(wu)(wu)氧化三(san)甲胺（TMAO）豐(feng)度升高(gao)，且較高(gao)的(de)(de)(de)(de)(de)血漿TMAO水平與較好(hao)的(de)(de)(de)(de)(de)免(mian)(mian)(mian)疫(yi)治療(liao)應(ying)(ying)答相關；細(xi)胞和(he)TNBC小鼠(shu)實驗(yan)表明，TMAO通過活(huo)化內(nei)質網應(ying)(ying)激激酶PERK來誘導GSDME介導的(de)(de)(de)(de)(de)癌細(xi)胞焦亡，從而增(zeng)強(qiang)CD8+ T細(xi)胞介導的(de)(de)(de)(de)(de)抗腫(zhong)瘤免(mian)(mian)(mian)疫(yi)；為TNBC小鼠(shu)補充(chong)膳食膽堿（TMAO前(qian)體(ti)）能(neng)(neng)提(ti)(ti)高(gao)腫(zhong)瘤TMAO水平，增(zeng)強(qiang)免(mian)(mian)(mian)疫(yi)治療(liao)應(ying)(ying)答。綜上所述，本(ben)研究提(ti)(ti)供了(le)共(gong)生菌(jun)群影響(xiang)宿(su)主(zhu)腫(zhong)瘤免(mian)(mian)(mian)疫(yi)能(neng)(neng)力的(de)(de)(de)(de)(de)新視(shi)角(jiao)。特(te)定(ding)的(de)(de)(de)(de)(de)微生物(wu)(wu)代謝產(chan)物(wu)(wu)及其前(qian)體(ti)分子可作為調節(jie)腫(zhong)瘤免(mian)(mian)(mian)疫(yi)微環境，從而改善TNBC免(mian)(mian)(mian)疫(yi)治療(liao)效果的(de)(de)(de)(de)(de)潛在干預(yu)策略。因此，微生物(wu)(wu)代謝產(chan)物(wu)(wu)TMAO可能(neng)(neng)具有(you)提(ti)(ti)高(gao)TNBC免(mian)(mian)(mian)疫(yi)治療(liao)效果的(de)(de)(de)(de)(de)臨床潛力，為TNBC的(de)(de)(de)(de)(de)精準免(mian)(mian)(mian)疫(yi)治療(liao)提(ti)(ti)供了(le)新的(de)(de)(de)(de)(de)思路(lu)；

《Biomaterials》：肽-AIEgen納米復合材(cai)料介導的全腫(zhong)瘤免疫循(xun)環-級(ji)聯擴增(zeng)改善腫(zhong)瘤免疫治療(liao)

英文題(ti)目：A peptide-AIEgen nanocomposite mediated whole cancer immunity cycle-cascade amplification for improved immunotherapy of tumor

期(qi)刊名：Biomaterials

影(ying)響因子：12.8

組學(xue)技(ji)術：RNA-Seq

主要研究結果：本(ben)研究設計了(le)一(yi)種級聯放大納米復合材料，PMRA/Poly(I:C)參與癌癥(zheng)免(mian)疫(yi)(yi)循環(huan)的(de)(de)六個步驟。通過全面改(gai)(gai)善(shan)腫(zhong)(zhong)(zhong)瘤免(mian)疫(yi)(yi)循環(huan)，極大地提(ti)(ti)高了(le)抗腫(zhong)(zhong)(zhong)瘤療效，ORR從(cong)不足(zu)30%提(ti)(ti)高到幾乎(hu)100%。從(cong)體內實驗結果來(lai)看，全癌癥(zheng)免(mian)疫(yi)(yi)循環(huan)強(qiang)化免(mian)疫(yi)(yi)治療促進了(le)50%的(de)(de)小鼠獲得長期生存。以(yi)PMRA/Poly(I:C)為起點，基于全癌癥(zheng)免(mian)疫(yi)(yi)循環(huan)增強(qiang)的(de)(de)策(ce)略可以(yi)進一(yi)步發展和(he)改(gai)(gai)進。綜上所述，我(wo)們(men)提(ti)(ti)出了(le)腫(zhong)(zhong)(zhong)瘤治療的(de)(de)全免(mian)疫(yi)(yi)循環(huan)增強(qiang)概念，有望為臨床上的(de)(de)腫(zhong)(zhong)(zhong)瘤治療策(ce)略提(ti)(ti)供參考。

《Advanced Science》：KK2DP7刺激脾(pi)臟中CD11b+細(xi)胞群引發(fa)抗腫瘤(liu)治療(liao)的(de)訓練免(mian)疫

英文(wen)題目：KK2DP7 Stimulates CD11b+ Cell Populations in the Spleen to Elicit Trained Immunity for Anti-Tumor Therapy

期刊名：Advanced Science

影響因子：14.3

組(zu)學技術：RNA-Seq、ATAC-Seq

主要研(yan)究結果：本研(yan)究發現KK2DP7可(ke)誘(you)導訓練(lian)免疫抑制腫瘤(liu)(liu)生長。脾臟(zang)CD11b+細胞(bao)(bao)是關鍵靶細胞(bao)(bao)。KK2DP7訓練(lian)可(ke)使CD11b+細胞(bao)(bao)的(de)免疫反應和細胞(bao)(bao)因子分泌通路激活，增(zeng)強細胞(bao)(bao)增(zeng)殖、吞(tun)噬和殺傷腫瘤(liu)(liu)細胞(bao)(bao)的(de)能(neng)力，且(qie)這(zhe)些變化受TLR2-IRF7信號軸調控(kong)。KK2DP7與(yu)免疫檢查點抑制劑(ji)抗體聯合使用，抗腫瘤(liu)(liu)效果(guo)更優(you)。樹突狀肽KK2DP7作(zuo)為模型(xing)佐劑(ji)給藥后可(ke)以刺(ci)激脾臟(zang)中的(de)CD11b+細胞(bao)(bao)群，激發針(zhen)對(dui)腫瘤(liu)(liu)治療的(de)訓練(lian)免疫。

參考文獻

[1]Liu J, Chen Q, Feng L, Liu Z. Nanomedicine for tumor microenvironment modulation and cancer treatment enhancement. Nano Today. 2018;21:55‐73

[2]De Visser KE, Joyce JA. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell. 2023 Mar 13;41(3):374-403. doi: 10.1016/j.ccell.2023.02.016. PMID: 36917948.

[3]Oiseth, S. J. & Aziz, M. S. A.-E. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J. Cancer Metastasis Treat. 3, 250–261 (2017).

[4]Balkwill, F. & Mantovani, A. Inflammation and cancer: back to Virchow? Lancet 357, 539–545 (2001).

[5]Adams, J., Smothers, J., Srinivasan, R. et al. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov 14, 603–622 (2015). //doi.org/10.1038/nrd4596