Cited by 965Cancer Immunotherapy and BiomarkersImmunotherapy and Immune ResponsesT-cell and B-cell Immunology

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Combination cancer immunotherapies tailored to the tumour microenvironment

Smyth, Mark J., Ngiow, Shin Foong, Ribas, Antoni, Teng, Michele W. L.·2016·Nature Reviews Clinical Oncology

DOI 10.1038/nrclinonc.2015.209

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Abstract

Evidence suggests that cancer immunotherapy will be a major part of the combination treatment plan for many patients with many cancer types in the near future. There are many types of immune processes involving different antitumour and tumour-promoting leucocytes, and tumour cells use many strategies to evade the immune response. The tumour microenvironment can help determine which immune suppressive pathways become activated to restrain antitumour immunity. This includes immune checkpoint receptors on effector T-cells and myeloid cells, and release of inhibitory cytokines and metabolites. Therapeutic approaches that target these pathways, particularly immune-checkpoint receptors, can induce durable antitumour responses in patients with advanced-stage cancers, including melanoma. Nevertheless, many patients do not have a good response to monotherapy approaches and alternative strategies are required to achieve optimal therapeutic benefit. These strategies include eliminating the bulk of tumour cells to provoke tumour-antigen release and antigen-presenting cell (APC) function, using adjuvants to enhance APC function, and using agents that enhance effector-cell activity. In this Review, we discuss the stratification of the tumour microenvironment according to tumour-infiltrating lymphocytes and PD-L1 expression in the tumour, and how this stratification enables the design of optimal combination cancer therapies tailored to target different tumour microenvironments.

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Tumor-Intrinsic or Drug-Induced Immunogenicity Dictates the Therapeutic Success of the PD1/PDL Axis Blockade
Rossi, A., Lucarini, V., Macchia, I., Sestili, P., Buccione, C., Donati, S., Ciccolella, M., Sistigu, A., D’Urso, M. T., Pacca, A. M., et al. (2020) · Cells · doi:10.3390/cells9040940 · Cited by 9
“Primary resistance to ICIs has been attributed to intrinsic properties of some tumors such as a low mutational burden [7–9], defective antigen presentation [10], and limited tumor infiltration [11].”
Background
Semiconducting Polymer Nano‐regulators with Cascading Activation for Photodynamic Cancer Immunotherapy
He, S., Liu, J., Zhang, C., Wang, J., & Pu, K. (2021) · Angewandte Chemie · doi:10.1002/ange.202116669 · Cited by 9
Hydroxyproline metabolism enhances IFN-γ-induced PD-L1 expression and inhibits autophagic flux
Spangenberg, S. H., Palermo, A., Gazaniga, N. R., Martínez‐Peña, F., Guijas, C., Chin, E. N., Rinschen, M. M., Sander, P. N., Webb, B., Pereira, L. E., et al. (2023) · Cell chemical biology · doi:10.1016/j.chembiol.2023.06.016 · Cited by 10
Nanoparticles targeting the adenosine pathway for cancer immunotherapy
Jiang, K., Wu, J., Wang, Q., Chen, X., Zhang, Y., Gu, X., & Tang, K. (2024) · Journal of Materials Chemistry B · doi:10.1039/d4tb00292j · Cited by 9
Immunotherapy in Colorectal Cancer
Mak, G., Moschetta, M., & Arkenau, H. (2016) · InTech eBooks · doi:10.5772/63136 · Cited by 9
“Overall, tumour cells are able to shape the host microenvironment, which is rich of immune cell populations, in a suitable way for them to survive to the host immune system recognition [10, 11].”
Background
New insight into cancer immunotherapy
Escribese, M. M., & Barber, D. (2017) · Allergologia et Immunopathologia · doi:10.1016/j.aller.2017.09.013 · Cited by 9
The good, the (not so) bad and the ugly of immune homeostasis in melanoma
Duarte, J. D. G., Woods, K., Andrews, M. C., & Behren, A. (2018) · Immunology and Cell Biology · doi:10.1111/imcb.12001 · Cited by 9
Novel chemical compound SINCRO with dual function in STING ‐type I interferon and tumor cell death pathways
Kimura, Y., Negishi, H., Matsuda, A., Endo, N., Hangai, S., Inoue, A., Nishio, J., Taniguchi, T., & Yanai, H. (2018) · Cancer Science · doi:10.1111/cas.13726 · Cited by 9
“With recent advances in T‐cell–mediated cancer immunotherapies, much attention has been focused on ways to harness immune responses against cancers.(1,2) In the context of the regulation of antitumor immunity by innate immune receptors, STING has been shown to play critical roles in the activation of antitumor T‐cell…”
Background
The Expression Level of PD-L1 (CD274) mRNA in Peripheral Blood Is a Potential Biomarker for Predicting Recurrence in Breast Cancer
Masuda, T., Noda, M., Kitagawa, A., Hu, Q., Fujii, A., Ito, S., Kosai, K., ANDO, Y., Matsumoto, Y., Ohtsu, H., et al. (2020) · Anticancer Research · doi:10.21873/anticanres.14362 · Cited by 9
Preliminary application of 125I–nivolumab to detect PD-1 expression in colon cancer via SPECT
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Bioinformatics analysis of an immunotherapy responsiveness-related gene signature in predicting lung adenocarcinoma prognosis
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PARP11 inhibition inactivates tumor-infiltrating regulatory T cells and improves the efficacy of immunotherapies
Basavaraja, R., Zhang, H., Holczbauer, Á., Lu, Z. F., Radaelli, E., Assenmacher, C., George, S. S., Nallamala, V. C., Beiting, D. P., Meyer‐Ficca, M. L., et al. (2024) · Cell Reports Medicine · doi:10.1016/j.xcrm.2024.101649 · Cited by 8
Self-luminous nanoengineered bacteria with the sustained release of interleukin 2 as an in situ vaccine for enhanced cancer immunotherapy
Liu, G., Wang, H., Fei, Z., Tao, X., Zheng, J., Cai, G., Li, X., Zhuang, J., & Ren, H. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.03.046 · Cited by 8
Dual‐Responsive Immunomodulatory RNAi Nanoplatform for Effective Immune Checkpoint Blockade and Enhanced Cancer Immunotherapy
Cao, Y., Zhao, Z., Fang, J., Lu, Y., Huang, Z., Wu, G., Gao, Q., Li, R., Xu, L., & Xu, X. (2025) · Advanced Healthcare Materials · doi:10.1002/adhm.202500646 · Cited by 8
Mitochondrial-targeted photodynamic therapy combined with TGF-β inhibition potentiates anti-PD-1 therapy in pancreatic ductal adenocarcinoma
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“This challenge has sparked a growing interest in rational combination strategies that can initiate tumor cell death and reprogram the immune landscape [27].”
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Immunotherapeutic strategies to induce inflection in the immune response: therapy for cancer and COVID-19
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“The immune checkpoint receptors that act as the primary targets of clinical cancer immunotherapy include cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), lymphocyte activation gene 3 (LAG-3), B and T lymphocyte attenuator (BTLA), and…”
Immunotherapy for HCC: limitations in patients with NASH
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Parys, M., Bavčar, Š., Mellanby, R. J., Argyle, D. J., & Kitamura, T. (2023) · PLoS ONE · doi:10.1371/journal.pone.0279057 · Cited by 8
“However, their efficacies are limited to a fraction of patients likely due to suppressive effects of tumor microenvironment on immune system [2, 3].”
Background
Tumour-associated macrophages as a potential target to improve natural killer cell-based immunotherapies
Kitamura, T. (2023) · Essays in Biochemistry · doi:10.1042/ebc20230002 · Cited by 8
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Peng, M., Dong, H., Shao, M., Zhang, X., Sun, J., Ding, C., Han, X., Yang, Q., Sang, X., & Cao, G. (2024) · Journal of Controlled Release · doi:10.1016/j.jconrel.2024.01.022 · Cited by 8
Revisiting 'Hallmarks of Cancer' In Sarcomas
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“…of the TIME through genomic instability and following neoantigen generation, T cell recognition and resultant tumor cell immunosuppressive programs could stratify tumors with different TIMEs that brings implications for cancer immunotherapy strategies in sarcomas in the future [106, 107].”
Background
The Era of Checkpoint Inhibition: Lessons Learned from Melanoma
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“The mechanism of action and clinical efficacy of anti PD-1 therapies have been extensively studied and reviewed elsewhere (11, 12).”
Background
Targeting IL-17alpha to promote anti-PD-1 therapy effect by screening the tumor immune microenvironment in a mouse oral carcinogenesis model
Wang, S., Yu, X., Li, F., Fan, H., Zhao, E., & Hu, Z. (2021) · Cancer Biomarkers · doi:10.3233/cbm-203092 · Cited by 8
“Interestingly, increased cytokine levels have been associated with resistance to targeted therapies [19,20].”
Neoadjuvant/Perioperative Treatment Affects Spatial Distribution and Densities of Tumor Associated Neutrophils and CD8+ Lymphocytes in Gastric Cancer
Hoffmann, A., Behrens, H., Heckl, S. M., Krüger, S., Becker, T., & Röcken, C. (2021) · Journal of Personalized Medicine · doi:10.3390/jpm11111184 · Cited by 9
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Background
Targeting immune checkpoints: Building better therapeutic puzzle in pancreatic cancer combination therapy
Abdkarimi, S., Soofiyani, S. R., Elham, G., Abdolahi, H. M., Safarzadeh, E., & Baradaran, B. (2020) · European Journal of Cancer Care · doi:10.1111/ecc.13268 · Cited by 9
Esophageal Diseases
Fitzgerald, R. C., & Vaezi, M. F. (2017) · Gastroenterology · doi:10.1053/j.gastro.2017.12.017 · Cited by 8
“While there is much work to be done, better molecular stratification of patients according to their likely response should improve outcomes and immune checkpoint inhibitors appear to have some activity.(37) It is our hope that these articles will be a useful and comprehensive reference source for new and experienced r…”
Background
Metal-based biomaterials for cancer gene therapy
Li, S., Zhang, C., Xu, X., Wang, X., Ren, H., Sun, B., & Zhang, Y. (2025) · Coordination Chemistry Reviews · doi:10.1016/j.ccr.2025.216720 · Cited by 7
Unraveling the alterations and biomarkers in the tumor microenvironment in lung adenocarcinoma metastases and their indications for therapeutic response and prognosis
Guan, C., Li, X., Zeng, X., Du, Z., Zhou, Z., Zhao, J., Song, L., & Yu, L. (2025) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359251403904 · Cited by 7
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“The goal of combination approaches, targeting several steps of the cancer-immunity cycle, is to CA209-067 n + i = 314 n = 316 n + i = 11.5 n = 6.93 HR 0.79 CA209-227 (PFS TMB High) n + i = 101 n = 102 1 yr n + i = 42% n = 29% HR 0.75 CA209-227 (PFS PD-L1 > 1”
Influential
Thyroid cancer risk prediction model using m6A RNA methylation regulators: integrated bioinformatics analysis and histological validation
Zhou, W., Lin, J., Liu, J., Zhang, R., Fan, A., Xie, Q., Liu, H., & Fan, D. (2023) · Aging · doi:10.18632/aging.204525 · Cited by 7
Unsolvable Problems of Biology: It Is Impossible to Create Two Identical Organisms, to Defeat Cancer, or to Map Organisms onto Their Genomes
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mRNA expression of programmed cell death ligand 1 and components of the phosphatidylinositol 3-kinase/AKT/phosphatase and tensin homolog pathway in epidermal growth factor receptor mutation-positive lung adenocarcinoma
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From Interconnection between Genes and Microenvironment to Novel Immunotherapeutic Approaches in Upper Gastro-Intestinal Cancers—A Multidisciplinary Perspective
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Background
Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer
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“Furthermore, inflammation in the hypoxic TME provokes immune tolerance via tumor- and T-cell expression of immune checkpoint proteins [13,14].”
Background
Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes
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“When used in combination with immunotherapy, this has achieved significant survival benefit for select patient subgroups [7].”
Method
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Identification of BST2 Contributing to the Development of Glioblastoma Based on Bioinformatics Analysis
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Tripartite antigen-agnostic combination immunotherapy cures established poorly immunogenic tumors
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Safety and Efficacy Analysis of PD-1 Inhibitors in Combination with Chemotherapy for Advanced Pancreatic Cancer
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Authors: Smyth, M. J., Ngiow, S. F., Ribas, A., & Teng, M. W. L.
Affiliations: QIMR Berghofer Medical Research Institute (AU)
University of California, Los Angeles (US)
Corresponding author: Teng, Michele W. L.
ORCID: Smyth, Mark J.
Ngiow, Shin Foong
Ribas, Antoni
Teng, Michele W. L.
Venue: Nature Reviews Clinical Oncology
Publisher: Springer Science and Business Media LLC
Published: 2015-11-24
Volume: 13
Issue: 3
Pages: 143-158
ISSN: 1759-4774 (ISSN-L)
1759-4782
DOI: 10.1038/nrclinonc.2015.209
OpenAlex: W2257916459
Cited by: 944
References: 218
Citations by year: 2026: 28 · 2025: 50 · 2024: 71 · 2023: 82 · 2022: 132 · 2021: 102 · 2020: 134 · 2019: 95 · 2018: 99 · 2017: 89 · 2016: 56 · 2015: 3
FWCI: 8.83
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Reviews Clinical Oncology (publishedVersion)
PubMed (publishedVersion)
Funders: Amgen
Bristol-Myers Squibb
Kite Pharma
National Cancer Institute (R35CA197633)
Topics: Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
Keywords: cancer immunotherapy, combination therapy, tumor microenvironment, immune evasion, immune checkpoint receptors, PD-L1, tumor-infiltrating lymphocytes, myeloid cells, inhibitory cytokines, antigen-presenting cells, adjuvants, melanoma
MeSH terms: Adjuvants, Immunologic, Animals, Antibodies, Monoclonal, Antineoplastic Combined Chemotherapy Protocols, Humans, Immunotherapy, Neoplasms, Signal Transduction, Treatment Outcome, Tumor Escape, Molecular Targeted Therapy, Tumor Microenvironment, B7-H1 Antigen

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Combination cancer immunotherapies tailored to the tumour microenvironment

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