从微环境视角看胰腺癌治疗：化疗、放疗与 靶向基质干预
Pancreatic Cancer Treatment from the Perspective of the Microenvironment: Chemotherapy, Radiotherapy, and Targeted Stromal Intervention
摘要: 胰腺导管腺癌(PDAC)因高度纤维化的肿瘤微环境(TME)导致“冷肿瘤”特征，形成免疫抑制与药物递送障碍的双重治疗瓶颈。微环境中癌症相关成纤维细胞(CAFs)通过分泌胶原蛋白、Wnt16及趋化因子，构建物理屏障并抑制T细胞浸润，使吉西他滨联合白蛋白紫杉醇(AG方案)的5年总生存率仅38%。靶向基质的Hedgehog通路抑制剂(如vismodegib)单用或联用化疗未能改善生存期(OS 6.9 vs 6.1个月)。近年突破性研究显示，多维度联合策略可突破耐药：立体定向放疗(SABR)联合PD-1抑制剂(帕博利珠单抗)和MEK抑制剂(曲美替尼)，使中位PFS提升至8.2个月(对照组5.4个月)，疾病进展风险降低40%；派安普利单抗联合阿洛替尼及PAAG方案(nab-紫杉醇/吉西他滨)的中位OS达13.7个月，显著优于传统AG方案(12个月OS率25%)。未来需基于间质亚型分型优化多靶点协同治疗，重塑TME以提升疗效。
Abstract: Pancreatic ductal adenocarcinoma (PDAC) exhibits a “cold tumor” microenvironment characterized by dense fibrosis and immunosuppression, creating dual barriers to drug delivery and immune infiltration. In the microenvironment, cancer-associated fibroblasts (CAFs) secrete collagen, Wnt16, and chemokines, creating a physical barrier and inhibiting T-cell infiltration. As a result, the 5-year overall survival rate of the gemcitabine combined with nab-paclitaxel (AG regimen) is only 38%. Targeting the stroma via Hedgehog pathway inhibitors (e.g., vismodegib) failed to improve survival (OS: 6.9 vs. 6.1 months) when combined with chemotherapy. Recent breakthroughs highlight multi-modal strategies: SABR combined with PD-1 inhibitor (pembrolizumab) and MEK inhibitor (trametinib) achieved a median PFS of 8.2 months (vs. 5.4 months in control), reducing disease progression risk by 40%. Similarly, anti-PD-1 (penpulimab) plus angiogenesis inhibitor (anlotinib) with PAAG regimen demonstrated a median OS of 13.7 months, significantly outperforming AG (12-month OS: 25%). These results underscore that integrating stromal modulation, vascular normalization, and immune checkpoint blockade can remodel the “cold” TME, enabling effective drug delivery and sustained T-cell activation. Future therapies should prioritize personalized stromal subtyping and optimized multi-target combinations to overcome resistance while ensuring safety, paving the way for durable survival benefits in PDAC.
文章引用：米锦超, 朱洪. 从微环境视角看胰腺癌治疗：化疗、放疗与 靶向基质干预[J]. 临床医学进展, 2026, 16(3): 2775-2783. https://doi.org/10.12677/acm.2026.1631078

参考文献

[1] Siegel, R.L., Giaquinto, A.N. and Jemal, A. (2024) Cancer Statistics, 2024. CA: A Cancer Journal for Clinicians, 74, 12-49. [Google Scholar] [CrossRef] [PubMed]
[2] Huang, J., Lok, V., Ngai, C.H., Zhang, L., Yuan, J., Lao, X.Q., et al. (2021) Worldwide Burden Of, Risk Factors For, and Trends in Pancreatic Cancer. Gastroenterology, 160, 744-754. [Google Scholar] [CrossRef] [PubMed]
[3] Zhang, Y., Crawford, H.C. and Pasca di Magliano, M. (2019) Epithelial-Stromal Interactions in Pancreatic Cancer. Annual Review of Physiology, 81, 211-233. [Google Scholar] [CrossRef] [PubMed]
[4] Clark, C.E., Hingorani, S.R., Mick, R., Combs, C., Tuveson, D.A. and Vonderheide, R.H. (2007) Dynamics of the Immune Reaction to Pancreatic Cancer from Inception to Invasion. Cancer Research, 67, 9518-9527. [Google Scholar] [CrossRef] [PubMed]
[5] Provenzano, P.P., Cuevas, C., Chang, A.E., Goel, V.K., Von Hoff, D.D. and Hingorani, S.R. (2012) Enzymatic Targeting of the Stroma Ablates Physical Barriers to Treatment of Pancreatic Ductal Adenocarcinoma. Cancer Cell, 21, 418-429. [Google Scholar] [CrossRef] [PubMed]
[6] Beatty, G.L., Werba, G., Lyssiotis, C.A. and Simeone, D.M. (2021) The Biological Underpinnings of Therapeutic Resistance in Pancreatic Cancer. Genes & Development, 35, 940-962. [Google Scholar] [CrossRef] [PubMed]
[7] Kim, M.P. and Gallick, G.E. (2008) Gemcitabine Resistance in Pancreatic Cancer: Picking the Key Players. Clinical Cancer Research, 14, 1284-1285. [Google Scholar] [CrossRef] [PubMed]
[8] Liu, L., Huang, X., Shi, F., Song, J., Guo, C., Yang, J., et al. (2022) Combination Therapy for Pancreatic Cancer: Anti-Pd-(l)1-Based Strategy. Journal of Experimental & Clinical Cancer Research, 41, Article No. 56. [Google Scholar] [CrossRef] [PubMed]
[9] Nywening, T.M., Wang-Gillam, A., Sanford, D.E., Belt, B.A., Panni, R.Z., Cusworth, B.M., et al. (2016) Targeting Tumour-Associated Macrophages with CCR2 Inhibition in Combination with FOLFIRINOX in Patients with Borderline Resectable and Locally Advanced Pancreatic Cancer: A Single-Centre, Open-Label, Dose-Finding, Non-Randomised, Phase 1b Trial. The Lancet Oncology, 17, 651-662. [Google Scholar] [CrossRef] [PubMed]
[10] Mills, B.N., Qiu, H., Drage, M.G., Chen, C., Mathew, J.S., Garrett-Larsen, J., et al. (2022) Modulation of the Human Pancreatic Ductal Adenocarcinoma Immune Microenvironment by Stereotactic Body Radiotherapy. Clinical Cancer Research, 28, 150-162. [Google Scholar] [CrossRef] [PubMed]
[11] Li, Z., Sun, C. and Qin, Z. (2021) Metabolic Reprogramming of Cancer-Associated Fibroblasts and Its Effect on Cancer Cell Reprogramming. Theranostics, 11, 8322-8336. [Google Scholar] [CrossRef] [PubMed]
[12] Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A.S., Ponz-Sarvise, M., et al. (2017) Distinct Populations of Inflammatory Fibroblasts and Myofibroblasts in Pancreatic Cancer. Journal of Experimental Medicine, 214, 579-596. [Google Scholar] [CrossRef] [PubMed]
[13] Huang, H. and Brekken, R.A. (2020) Recent Advances in Understanding Cancer-Associated Fibroblasts in Pancreatic Cancer. American Journal of Physiology-Cell Physiology, 319, C233-C243. [Google Scholar] [CrossRef] [PubMed]
[14] Uzunparmak, B. and Sahin, I.H. (2019) Pancreatic Cancer Microenvironment: A Current Dilemma. Clinical and Translational Medicine, 8, Article No. 2. [Google Scholar] [CrossRef] [PubMed]
[15] DuFort, C.C., DelGiorno, K.E., Carlson, M.A., Osgood, R.J., Zhao, C., Huang, Z., et al. (2016) Interstitial Pressure in Pancreatic Ductal Adenocarcinoma Is Dominated by a Gel-Fluid Phase. Biophysical Journal, 110, 2106-2119. [Google Scholar] [CrossRef] [PubMed]
[16] Mariathasan, S., Turley, S.J., Nickles, D., Castiglioni, A., Yuen, K., Wang, Y., et al. (2018) TGFβ Attenuates Tumour Response to PD-L1 Blockade by Contributing to Exclusion of T Cells. Nature, 554, 544-548. [Google Scholar] [CrossRef] [PubMed]
[17] Zhang, P., Wang, J., Luo, W., Yuan, J., Cui, C., Guo, L., et al. (2021) Kindlin-2 Acts as a Key Mediator of Lung Fibroblast Activation and Pulmonary Fibrosis Progression. American Journal of Respiratory Cell and Molecular Biology, 65, 54-69. [Google Scholar] [CrossRef] [PubMed]
[18] Koong, A.C., Mehta, V.K., Le, Q.T., Fisher, G.A., Terris, D.J., Brown, J.M., et al. (2000) Pancreatic Tumors Show High Levels of Hypoxia. International Journal of Radiation Oncology, Biology, Physics, 48, 919-922. [Google Scholar] [CrossRef] [PubMed]
[19] Jing, X., Yang, F., Shao, C., Wei, K., Xie, M., Shen, H., et al. (2019) Role of Hypoxia in Cancer Therapy by Regulating the Tumor Microenvironment. Molecular Cancer, 18, Article No. 157. [Google Scholar] [CrossRef] [PubMed]
[20] Pereira, B.A., Vennin, C., Papanicolaou, M., Chambers, C.R., Herrmann, D., Morton, J.P., et al. (2019) CAF Subpopulations: A New Reservoir of Stromal Targets in Pancreatic Cancer. Trends in Cancer, 5, 724-741. [Google Scholar] [CrossRef] [PubMed]
[21] Norton, J., Foster, D., Chinta, M., Titan, A. and Longaker, M. (2020) Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment. Cancers, 12, Article 1347. [Google Scholar] [CrossRef] [PubMed]
[22] Feig, C., Jones, J.O., Kraman, M., Wells, R.J.B., Deonarine, A., Chan, D.S., et al. (2013) Targeting CXCL12 from Fap-Expressing Carcinoma-Associated Fibroblasts Synergizes with Anti-Pd-L1 Immunotherapy in Pancreatic Cancer. Proceedings of the National Academy of Sciences, 110, 20212-20217. [Google Scholar] [CrossRef] [PubMed]
[23] Qian, Y., Gong, Y., Fan, Z., Luo, G., Huang, Q., Deng, S., et al. (2020) Molecular Alterations and Targeted Therapy in Pancreatic Ductal Adenocarcinoma. Journal of Hematology & Oncology, 13, Article No. 130. [Google Scholar] [CrossRef] [PubMed]
[24] Fan, J., Wang, M., Chen, H., Shang, D., Das, J.K. and Song, J. (2020) Current Advances and Outlooks in Immunotherapy for Pancreatic Ductal Adenocarcinoma. Molecular Cancer, 19, Article No. 32. [Google Scholar] [CrossRef] [PubMed]
[25] Espinet, E., Klein, L., Puré, E. and Singh, S.K. (2022) Mechanisms of PDAC Subtype Heterogeneity and Therapy Response. Trends in Cancer, 8, 1060-1071. [Google Scholar] [CrossRef] [PubMed]
[26] Mhaidly, R. and Mechta‐Grigoriou, F. (2021) Role of Cancer‐Associated Fibroblast Subpopulations in Immune Infiltration, as a New Means of Treatment in Cancer. Immunological Reviews, 302, 259-272. [Google Scholar] [CrossRef] [PubMed]
[27] Peng, D., Fu, M., Wang, M., Wei, Y. and Wei, X. (2022) Targeting TGF-Β Signal Transduction for Fibrosis and Cancer Therapy. Molecular Cancer, 21, Article No. 104. [Google Scholar] [CrossRef] [PubMed]
[28] Gadwa, J., Amann, M., Bickett, T.E., Knitz, M.W., Darragh, L.B., Piper, M., et al. (2023) Selective Targeting of IL2Rβγ Combined with Radiotherapy Triggers CD8-and NK-Mediated Immunity, Abrogating Metastasis in HNSCC. Cell Reports Medicine, 4, Article 101150. [Google Scholar] [CrossRef] [PubMed]
[29] Piper, M., Hoen, M., Darragh, L.B., Knitz, M.W., Nguyen, D., Gadwa, J., et al. (2023) Simultaneous Targeting of PD-1 and IL-2Rβγ with Radiation Therapy Inhibits Pancreatic Cancer Growth and Metastasis. Cancer Cell, 41, 950-969.e6. [Google Scholar] [CrossRef] [PubMed]
[30] Spitzer, M.H., Carmi, Y., Reticker-Flynn, N.E., Kwek, S.S., Madhireddy, D., Martins, M.M., et al. (2017) Systemic Immunity Is Required for Effective Cancer Immunotherapy. Cell, 168, 487-502.e15. [Google Scholar] [CrossRef] [PubMed]
[31] Hiam-Galvez, K.J., Allen, B.M. and Spitzer, M.H. (2021) Systemic Immunity in Cancer. Nature Reviews Cancer, 21, 345-359. [Google Scholar] [CrossRef] [PubMed]
[32] De Jesus-Acosta, A., Sugar, E.A., O’Dwyer, P.J., Ramanathan, R.K., Von Hoff, D.D., Rasheed, Z., Zheng, L., Begum, A., Anders, R., Maitra, A., McAllister, F., Rajeshkumar, N.V., Yabuuchi, S., de Wilde, R.F., Batukbhai, B., Sahin, I. and Laheru, D.A. (2020) Phase 2 Study of Vismodegib, a Hedgehog Inhibitor, Combined with Gemcitabine and Nab-Paclitaxel in Patients with Untreated Metastatic Pancreatic Adenocarcinoma. British Journal of Cancer, 122, 498-505. [Google Scholar] [CrossRef] [PubMed]
[33] Kim, E.J., Sahai, V., Abel, E.V., Griffith, K.A., Greenson, J.K., Takebe, N., et al. (2014) Pilot Clinical Trial of Hedgehog Pathway Inhibitor GDC-0449 (Vismodegib) in Combination with Gemcitabine in Patients with Metastatic Pancreatic Adenocarcinoma. Clinical Cancer Research, 20, 5937-5945. [Google Scholar] [CrossRef] [PubMed]
[34] Halbrook, C.J., Lyssiotis, C.A., Pasca di Magliano, M. and Maitra, A. (2023) Pancreatic Cancer: Advances and Challenges. Cell, 186, 1729-1754. [Google Scholar] [CrossRef] [PubMed]
[35] Tang, R., Xu, J., Wang, W., Meng, Q., Shao, C., Zhang, Y., et al. (2023) Targeting Neoadjuvant Chemotherapy-Induced Metabolic Reprogramming in Pancreatic Cancer Promotes Anti-Tumor Immunity and Chemo-Response. Cell Reports Medicine, 4, Article 101234. [Google Scholar] [CrossRef] [PubMed]
[36] Zhang, J., Lv, S., Peng, X., Liu, H., Guo, J., Liu, Z., et al. (2025) Circerc1 Facilitates Chemoresistance through Inhibiting Pyroptosis and Remodeling Extracellular Matrix in Pancreatic Cancer. Molecular Cancer, 24, Article No. 185. [Google Scholar] [CrossRef] [PubMed]
[37] Lhuillier, C., Rudqvist, N., Elemento, O., Formenti, S.C. and Demaria, S. (2019) Radiation Therapy and Anti-Tumor Immunity: Exposing Immunogenic Mutations to the Immune System. Genome Medicine, 11, Article No. 40. [Google Scholar] [CrossRef] [PubMed]
[38] Lussier, D.M., Alspach, E., Ward, J.P., Miceli, A.P., Runci, D., White, J.M., et al. (2021) Radiation-Induced Neoantigens Broaden the Immunotherapeutic Window of Cancers with Low Mutational Loads. Proceedings of the National Academy of Sciences, 118, e2102611118. [Google Scholar] [CrossRef] [PubMed]
[39] Timmer, F.E.F., Geboers, B., Ruarus, A.H., Vroomen, L.G.P.H., Schouten, E.A.C., van der Lei, S., et al. (2024) Mri-guided Stereotactic Ablative Body Radiotherapy versus CT-Guided Percutaneous Irreversible Electroporation for Locally Advanced Pancreatic Cancer (CROSSFIRE): A Single-Centre, Open-Label, Randomised Phase 2 Trial. The Lancet Gastroenterology & Hepatology, 9, 448-459. [Google Scholar] [CrossRef] [PubMed]
[40] Kalbasi, A., Komar, C., Tooker, G.M., Liu, M., Lee, J.W., Gladney, W.L., et al. (2017) Tumor-Derived CCL2 Mediates Resistance to Radiotherapy in Pancreatic Ductal Adenocarcinoma. Clinical Cancer Research, 23, 137-148. [Google Scholar] [CrossRef] [PubMed]
[41] Russell, S.N., Demetriou, C., Valenzano, G., Evans, A., Go, S., Stanly, T., et al. (2025) Induction of Macrophage Efferocytosis in Pancreatic Cancer via PI3Kγ Inhibition and Radiotherapy Promotes Tumour Control. Gut, 74, 825-839. [Google Scholar] [CrossRef] [PubMed]
[42] Ye, J., Mills, B.N., Qin, S.S., Garrett-Larsen, J., Murphy, J.D., Uccello, T.P., et al. (2022) Toll-Like Receptor 7/8 Agonist R848 Alters the Immune Tumor Microenvironment and Enhances SBRT-Induced Antitumor Efficacy in Murine Models of Pancreatic Cancer. Journal for ImmunoTherapy of Cancer, 10, e004784. [Google Scholar] [CrossRef] [PubMed]
[43] Steele, N.G., Biffi, G., Kemp, S.B., Zhang, Y., Drouillard, D., Syu, L., et al. (2021) Inhibition of Hedgehog Signaling Alters Fibroblast Composition in Pancreatic Cancer. Clinical Cancer Research, 27, 2023-2037. [Google Scholar] [CrossRef] [PubMed]
[44] Cortes, J.E., Gutzmer, R., Kieran, M.W. and Solomon, J.A. (2019) Hedgehog Signaling Inhibitors in Solid and Hematological Cancers. Cancer Treatment Reviews, 76, 41-50. [Google Scholar] [CrossRef] [PubMed]
[45] Dai, W., Wu, X., Li, J., Tang, W., Wang, Y., Xu, W., et al. (2023) Hedgehog-Gli1-Derived Exosomal Circ-0011536 Mediates Peripheral Neural Remodeling in Pancreatic Cancer by Modulating the miR-451a/Vgf Axis. Journal of Experimental & Clinical Cancer Research, 42, Article No. 329. [Google Scholar] [CrossRef] [PubMed]
[46] Mpekris, F., Papageorgis, P., Polydorou, C., Voutouri, C., Kalli, M., Pirentis, A.P., et al. (2017) Sonic-Hedgehog Pathway Inhibition Normalizes Desmoplastic Tumor Microenvironment to Improve Chemo-and Nanotherapy. Journal of Controlled Release, 261, 105-112. [Google Scholar] [CrossRef] [PubMed]
[47] Zhao, J., Wang, H., Hsiao, C., Chow, D.S., Koay, E.J., Kang, Y., et al. (2018) Simultaneous Inhibition of Hedgehog Signaling and Tumor Proliferation Remodels Stroma and Enhances Pancreatic Cancer Therapy. Biomaterials, 159, 215-228. [Google Scholar] [CrossRef] [PubMed]
[48] Catenacci, D.V.T., Junttila, M.R., Karrison, T., Bahary, N., Horiba, M.N., Nattam, S.R., et al. (2015) Randomized Phase Ib/II Study of Gemcitabine Plus Placebo or Vismodegib, a Hedgehog Pathway Inhibitor, in Patients with Metastatic Pancreatic Cancer. Journal of Clinical Oncology, 33, 4284-4292. [Google Scholar] [CrossRef] [PubMed]
[49] Tempero, M., Oh, D., Tabernero, J., Reni, M., Van Cutsem, E., Hendifar, A., et al. (2021) Ibrutinib in Combination with Nab-Paclitaxel and Gemcitabine for First-Line Treatment of Patients with Metastatic Pancreatic Adenocarcinoma: Phase III RESOLVE Study. Annals of Oncology, 32, 600-608. [Google Scholar] [CrossRef] [PubMed]
[50] Neesse, A., Bauer, C.A., Öhlund, D., Lauth, M., Buchholz, M., Michl, P., et al. (2018) Stromal Biology and Therapy in Pancreatic Cancer: Ready for Clinical Translation? Gut, 68, 159-171. [Google Scholar] [CrossRef] [PubMed]
[51] Zhu, X., Cao, Y., Liu, W., Ju, X., Zhao, X., Jiang, L., et al. (2021) RETRACTION: Stereotactic Body Radiotherapy Plus Pembrolizumab and Trametinib versus Stereotactic Body Radiotherapy Plus Gemcitabine for Locally Recurrent Pancreatic Cancer after Surgical Resection: An Open-Label, Randomised, Controlled, Phase 2 Trial. The Lancet Oncology, 22, 1093-1102. [Google Scholar] [CrossRef] [PubMed]
[52] Sha, H., Tong, F., Ni, J., Sun, Y., Zhu, Y., Qi, L., et al. (2024) First-Line Penpulimab (An Anti-Pd1 Antibody) and Anlotinib (An Angiogenesis Inhibitor) with Nab-Paclitaxel/Gemcitabine (PAAG) in Metastatic Pancreatic Cancer: A Prospective, Multicentre, Biomolecular Exploratory, Phase II Trial. Signal Transduction and Targeted Therapy, 9, Article No. 143. [Google Scholar] [CrossRef] [PubMed]

为你推荐