Challenges and Recent Advances in NK Cell-Targeted Immunotherapies in Solid Tumors

Natural killer (NK) cell is a powerful malignant cells killer, providing rapid immune responses via direct cytotoxicity without the need of antigen processing and presentation. It plays an essential role in preventing early tumor, metastasis and minimal residual disease. Although adoptive NK therapies achieved great success in clinical trials against hematologic malignancies, their accumulation, activation, cytotoxic and immunoregulatory functions are severely impaired in the immunosuppressive microenvironment of solid tumors. Now with better understandings of the tumor evasive mechanisms from NK-mediated immunosurveillance, immunotherapies targeting the key molecules for NK cell dysfunction and exhaustion have been developed and tested in both preclinical and clinical studies. In this review, we introduce the challenges that NK cells encountered in solid tumor microenvironment (TME) and the therapeutic approaches to overcome these limitations, followed by an outline of the recent preclinical advances and the latest clinical outcomes of NK-based immunotherapies, as well as promising strategies to optimize current NK-targeted immunotherapies for solid tumors.

• Publication year

  2021

• Venue

  International Journal of Molecular Sciences

• Publication date

  2021-12-23

• Fields of study

  Medicine

• Identifiers
  DOI 10.3390/ijms23010164PMID 35008589PMCID 8745474
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Interferon Alfa-2b Adjuvant Therapy of High-Risk Resected Cutaneous Melanoma: The Eastern Cooperative Oncology Group Trial EST 1684

  2023cited by this paper
• Engineering NK Cells for CAR Therapy—Recent Advances in Gene Transfer Methodology

  2021cited by this paper
• Design of a Trispecific Checkpoint Inhibitor and Natural Killer Cell Engager Based on a 2 + 1 Common Light Chain Antibody Architecture

  2021cited by this paper
• Current status and perspective of CAR-T and CAR-NK cell therapy trials in Germany

  2021cited by this paper
• A HER2 Tri-Specific NK Cell Engager Mediates Efficient Targeting of Human Ovarian Cancer

  2021cited by this paper
• Preclinical evaluation of AFM24, a novel CD16A-specific innate immune cell engager targeting EGFR-positive tumors

  2021cited by this paper
• Immunomodulatory drugs activate NK cells via both Zap-70 and cereblon-dependent pathways

  2020cited by this paper
• Immunoediting of cancer metastasis by NK cells

  2020cited by this paper
• Influence of KIR and NK Cell Reconstitution in the Outcomes of Hematopoietic Stem Cell Transplantation

  2020cited by this paper
• iPSC-derived NK cells maintain high cytotoxicity and enhance in vivo tumor control in concert with T cells and anti–PD-1 therapy

  2020cited by this paper
• NK cells for cancer immunotherapy

  2020cited by this paper
• Exploring the NK cell platform for cancer immunotherapy

  2020cited by this paper
• The Tumor Microenvironment—A Metabolic Obstacle to NK Cells’ Activity

  2020cited by this paper
• The NK cell–cancer cycle: advances and new challenges in NK cell–based immunotherapies

  2020cited by this paper
• Influence of the Tumor Microenvironment on NK Cell Function in Solid Tumors

  2020cited by this paper
• A guide to cancer immunotherapy: from T cell basic science to clinical practice

  2020cited by this paper
• Single-Cell RNA Sequencing of Tumor-Infiltrating NK Cells Reveals that Inhibition of Transcription Factor HIF-1α Unleashes NK Cell Activity.

  2020cited by this paper
• Prognostic Significance of Tumor-Infiltrating Natural Killer Cells in Solid Tumors: A Systematic Review and Meta-Analysis

  2020cited by this paper
• Recent progress in and challenges in cellular therapy using NK cells for hematological malignancies.

  2020cited by this paper
• NK cell infiltration is associated with improved overall survival in solid cancers: A systematic review and meta-analysis

  2020cited by this paper
• One for all, All for one

  2019cited by this paper
• Delivery technologies for cancer immunotherapy

  2019cited by this paper
• Accumulation of Tumor-Infiltrating CD49a+ NK Cells Correlates with Poor Prognosis for Human Hepatocellular Carcinoma

  2019cited by this paper
• Improving cancer immunotherapy through nanotechnology

  2019cited by this paper
• Overcoming Resistance to Natural Killer Cell Based Immunotherapies for Solid Tumors

  2019influential reference
• Endometrial Tumor Microenvironment Alters Human NK Cell Recruitment, and Resident NK Cell Phenotype and Function

  2019influential reference
• Chronic stimulation drives human NK cell dysfunction and epigenetic reprograming.

  2019cited by this paper
• Prognostic value of TGF-β in lung cancer: systematic review and meta-analysis

  2019cited by this paper
• A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors.

  2019cited by this paper
• Multifunctional Natural Killer Cell Engagers Targeting NKp46 Trigger Protective Tumor Immunity.

  2019cited by this paper
• CD73 Immune Checkpoint Defines Regulatory NK-cells within the Tumor Microenvironment.

  2019cited by this paper
• Remodeling the Tumor Microenvironment Sensitizes Breast Tumors to Anti- Programmed Death-Ligand 1 Immunotherapy.

  2019cited by this paper
• Killers 2.0: NK cell therapies at the forefront of cancer control.

  2019cited by this paper
• The Natural Cytotoxicity Receptors in Health and Disease

  2019cited by this paper
• Engineering strategies to overcome the current roadblocks in CAR T cell therapy

  2019cited by this paper
• Immunometabolism and natural killer cell responses

  2019cited by this paper
• Killer Ig-Like Receptors (KIRs): Their Role in NK Cell Modulation and Developments Leading to Their Clinical Exploitation

  2019cited by this paper
• Monalizumab: inhibiting the novel immune checkpoint NKG2A

  2019cited by this paper
• CXCR1 Expression to Improve Anti-Cancer Efficacy of Intravenously Injected CAR-NK Cells in Mice with Peritoneal Xenografts

  2019cited by this paper
• NK cells switch from granzyme B to death receptor–mediated cytotoxicity during serial killing

  2019cited by this paper
• NK Cell Dysfunction and Checkpoint Immunotherapy

  2019cited by this paper
• NKp46 Receptor-Mediated Interferon-γ Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis

  2018cited by this paper
• Cancer immunologists scoop medicine Nobel prize

  2018cited by this paper
• Anti-NKG2A mAb Is a Checkpoint Inhibitor that Promotes Anti-tumor Immunity by Unleashing Both T and NK Cells

  2018cited by this paper
• Human iPSC-Derived Natural Killer Cells Engineered with Chimeric Antigen Receptors Enhance Anti-tumor Activity.

  2018cited by this paper
• Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy

  2018cited by this paper
• A2AR Adenosine Signaling Suppresses Natural Killer Cell Maturation in the Tumor Microenvironment.

  2018cited by this paper
• Avelumab, an IgG1 anti-PD-L1 Immune Checkpoint Inhibitor, Triggers NK Cell-Mediated Cytotoxicity and Cytokine Production Against Triple Negative Breast Cancer Cells

  2018cited by this paper
• Prostaglandin E2 Secreted by Thyroid Cancer Cells Contributes to Immune Escape Through the Suppression of Natural Killer (NK) Cell Cytotoxicity and NK Cell Differentiation

  2018cited by this paper
• Trispecific killer engager CD16xIL15xCD33 potently induces NK cell activation and cytotoxicity against neoplastic mast cells.

  2018cited by this paper
• Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression.

  2018cited by this paper
• Endogenous glucocorticoids control host resistance to viral infection through the tissue-specific regulation of PD-1 expression on NK cells

  2018cited by this paper
• Novel Human NK Cell Line Carrying CAR Targeting EGFRvIII Induces Antitumor Effects in Glioblastoma Cells

  2018cited by this paper
• Interferon-Gamma at the Crossroads of Tumor Immune Surveillance or Evasion

  2018cited by this paper
• Contribution of NK cells to immunotherapy mediated by PD-1/PD-L1 blockade

  2018cited by this paper
• Anti-ADAM17 monoclonal antibody MEDI3622 increases IFNγ production by human NK cells in the presence of antibody-bound tumor cells

  2018cited by this paper
• Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell–driven tumor immunity

  2018cited by this paper
• Cancer immunotherapy using checkpoint blockade

  2018cited by this paper
• Cord blood NK cells engineered to express IL-15 and a CD19-targeted CAR show long-term persistence and potent antitumor activity

  2018cited by this paper
• Enhanced Cancer Immunotherapy with Smad3-Silenced NK-92 Cells

  2018cited by this paper
• Complete Remission with Reduction of High-Risk Clones following Haploidentical NK-Cell Therapy against MDS and AML

  2018cited by this paper
• NKG2D and Its Ligands: “One for All, All for One”

  2018cited by this paper
• NKp46 Receptor‐Mediated Interferon‐&ggr; Production by Natural Killer Cells Increases Fibronectin 1 to Alter Tumor Architecture and Control Metastasis

  2018cited by this paper
• Nitric Oxide Production by Myeloid-Derived Suppressor Cells Plays a Role in Impairing Fc Receptor–Mediated Natural Killer Cell Function

  2018cited by this paper
• Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity

  2018cited by this paper
• Canonical TGF-β Signaling Pathway Represses Human NK Cell Metabolism

  2018cited by this paper
• Natural killer cell-mediated immunosurveillance of human cancer.

  2017cited by this paper
• Cord blood natural killer cells expressing a dominant negative TGF-β receptor: Implications for adoptive immunotherapy for glioblastoma.

  2017cited by this paper
• Targeting latency-associated peptide promotes antitumor immunity

  2017cited by this paper
• Umbilical Cord Blood Natural Killer Cells, Their Characteristics, and Potential Clinical Applications

  2017cited by this paper
• Targeting autophagy inhibits melanoma growth by enhancing NK cells infiltration in a CCL5-dependent manner

  2017cited by this paper
• Genetic engineering of human NK cells to express CXCR2 improves migration to renal cell carcinoma

  2017cited by this paper
• Clinical Pharmacology and Translational Aspects of Bispecific Antibodies

  2017cited by this paper
• Engineering of Anti-CD133 Trispecific Molecule Capable of Inducing NK Expansion and Driving Antibody-Dependent Cell-Mediated Cytotoxicity

  2017cited by this paper
• A Two-Phase Expansion Protocol Combining Interleukin (IL)-15 and IL-21 Improves Natural Killer Cell Proliferation and Cytotoxicity against Rhabdomyosarcoma

  2017cited by this paper
• Immunoregulatory Role of NK Cells in Tissue Inflammation and Regeneration

  2017cited by this paper
• Allogeneic NK cells eradicate myeloblasts but not neoplastic mast cells in systemic mastocytosis associated with acute myeloid leukemia

  2017cited by this paper
• Smad3 promotes cancer progression by inhibiting E4BP4-mediated NK cell development

  2017cited by this paper
• Antibody Tumor Targeting Is Enhanced by CD27 Agonists through Myeloid Recruitment

  2017cited by this paper
• NK Cell Exhaustion

  2017cited by this paper
• NK Cells in Cancer Immunotherapy

  2017cited by this paper
• High TGF-β1 expression predicts poor disease prognosis in hepatocellular carcinoma patients

  2017cited by this paper
• Role of Platelet-Derived Tgfβ1 in the Progression of Ovarian Cancer

  2017cited by this paper
• “Multi-Omics” Analyses of the Development and Function of Natural Killer Cells

  2017cited by this paper
• IL-1R8 is a checkpoint in NK cells regulating anti-tumor and anti-viral activity

  2017cited by this paper
• Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cells

  2017cited by this paper
• Prognostic value of transforming growth factor-beta in patients with colorectal cancer who undergo surgery: a meta-analysis

  2017cited by this paper
• Tetraspecific scFv construct provides NK cell mediated ADCC and self-sustaining stimuli via insertion of IL-15 as a cross-linker

  2016cited by this paper
• Metabolic Reprogramming Supports IFN-γ Production by CD56bright NK Cells

  2016cited by this paper
• Targeting natural killer cells in cancer immunotherapy

  2016cited by this paper
• Heterodimeric Bispecific Single Chain Variable Fragments (scFv) Killer Engagers (BiKEs) Enhance NK-cell Activity Against CD133+ Colorectal Cancer Cells

  2016cited by this paper
• Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation.

  2016cited by this paper
• Human Circulating and Tissue-Resident CD56bright Natural Killer Cell Populations

  2016cited by this paper
• Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

  2016cited by this paper
• Repression of GSK3 restores NK cell cytotoxicity in AML patients

  2016cited by this paper
• Natural Killer Cells for Immunotherapy – Advantages of the NK-92 Cell Line over Blood NK Cells

  2016cited by this paper
• A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases

  2016cited by this paper
• LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

  2016cited by this paper
• Human liver-resident CD56(bright)/CD16(neg) NK cells are retained within hepatic sinusoids via the engagement of CCR5 and CXCR6 pathways.

  2016cited by this paper
• TGF-β inhibits the activation and functions of NK cells by repressing the mTOR pathway

  2016cited by this paper

• Mechanotransduction of Piezo1 in the cancer microenvironment: implications for NK cell-based immunotherapy

  2026cites this paper
• From innate immunity to precision cancer therapy: the clinical advancement of NK cell therapy.

  2026cites this paper
• Single-cell dissection of hepatocellular carcinoma immunity: from heterogeneous subtypes to precision therapeutics.

  2026cites this paper
• Advances and Challenges in CAR-NK Cell Therapy for Tumor Immunotherapy

  2025cites this paper
• Mitochondrial dynamics and metabolic attributes regulate function of natural killer cell and infiltration in tumor microenvironment modulating disease progression.

  2025cites this paper
• Harnessing the chimeric antigen receptor engineered cells in gastrointestinal cancer immunotherapy.

  2025cites this paper
• Ethical and Regulatory Considerations in the Clinical Translation of Pluripotent Stem Cell-Derived NK Cell Therapies.

  2025cites this paper
• Influence of Genetic, Dietary, and Environmental Factors on Natural Killer (NK) Cell Biology and Function: Interplay Between NK Cell Activity and Cancer Onset or Progression

  2025cites this paper
• Nanotechnology and natural killer cell immunotherapy: synergistic approaches for precise immune system adjustment and targeted cancer treatment in gastrointestinal tumors

  2025cites this paper
• Exosomes derived from natural killer cells: transforming immunotherapy for aggressive breast cancer

  2025cites this paper
• CAR-NK cell therapy: promise and challenges in solid tumors

  2025cites this paper
• NK cell activity in the tumor microenvironment

  2025cites this paper
• Advancing CAR-based cell therapies for solid tumours: challenges, therapeutic strategies, and perspectives

  2025cites this paper
• Natural killer cell therapy in hepatocellular carcinoma: a comprehensive review

  2025cites this paper
• The Effect of Iron Deficiency on Immune Parameters, Including Memory B Cells and Infection Presentations: A Cohort Study in Premenopausal Women

  2025cites this paper
• Anthocyanin-functionalized selenocysteine nanotherapeutics alleviate cisplatin nephrotoxicity by inhibiting oxidative stress and ferroptosis

  2025cites this paper
• Mechanical Vibration-Induced Change in Stiffness of Breast Cancer Cells Promotes Natural Killer Cell-Mediated Tumor Killing Activity.

  2025cites this paper
• The advantages of NK cell vaccines in solid carcinoma clinical trials: conducted by various biology strategy and technology

  2025cites this paper
• A triple combination strategy for nasopharyngeal carcinoma: Aptamer-guided liposomal chemotherapy, engineered NK cells, and Fc-enhanced PD-L1 antibody therapy

  2025cites this paper
• Current landscape of clinical use of ex vivo expanded natural killer cells for cancer therapy

  2024cites this paper
• Advanced Strategies of CAR-T Cell Therapy in Solid Tumors and Hematological Malignancies.

  2024cites this paper
• Enhanced tumor control activities of anti-mPD-L1 antibody and antigen-presenting cell-like natural killer cell in an allograft model

  2024cites this paper
• Adoptive cell therapy for solid tumors beyond CAR-T: Current challenges and emerging therapeutic advances.

  2024cites this paper
• Enhancing the Anti-Tumor Efficacy of NK Cells on Canine Mammary Tumors through Resveratrol Activation

  2024cites this paper
• Disrupting Smad3 potentiates immunostimulatory function of NK cells against lung carcinoma by promoting GM-CSF production

  2024cites this paper
• Contemporary Approaches to Immunotherapy of Solid Tumors

  2024cites this paper
• Harnessing the Power of NK Cell Receptor Engineering as a New Prospect in Cancer Immunotherapy

  2024cites this paper
• Finding potential targets in cell-based immunotherapy for handling the challenges of acute myeloid leukemia.

  2024cites this paper
• Commentary: On the Emerging Role of Innate Lymphoid Cells in Bladder Cancer

  2024cites this paper
• Current Developments in NK Cell Engagers for Cancer Immunotherapy: Focus on CD16A and NKp46

  2024influential citation
• Natural killer cell-based therapies in neuroblastoma.

  2024cites this paper
• The Evolving Applications of Bispecific Antibodies: Reaping the Harvest of Early Sowing and Planting New Seeds

  2024cites this paper
• Research Status of NK Cell Therapy for Solid Tumors

  2024cites this paper
• Decoding the Natural Killer Cell Enigma: A Review

  2024cites this paper
• Mechanisms underlying the efficacy and safety of IgG, antibody fragments, and design immune-biologics.

  2023cites this paper
• Investigation of the efficacy and feasibility of combined therapy of PD‐L1‐enhanced exogenous peripatetic adoptive natural killer (NK) cells in combination with antiangiogenic targeted therapy in the treatment of extensive‐stage small cell lung cancer

  2023cites this paper
• The application, safety, and future of ex vivo immune cell therapies and prognosis in different malignancies

  2023cites this paper
• WTAP enhances the instability of SYTL1 mRNA caused by YTHDF2 in bladder cancer.

  2023cites this paper
• T cells, NK cells, and tumor-associated macrophages in cancer immunotherapy and the current state of the art of drug delivery systems

  2023cites this paper
• Cancer immunotherapy via stem cell-derived NK cells.

  2023cites this paper
• Murine models to study human NK cells in human solid tumors

  2023cites this paper
• Update on immune‐based therapy strategies targeting cancer stem cells

  2023cites this paper
• Opportunities and challenges of natural killer cell-derived extracellular vesicles

  2023cites this paper
• The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

  2023cites this paper
• (Dis)similarities between the Decidual and Tumor Microenvironment

  2022cites this paper
• ZL-1211 Exhibits Robust Antitumor Activity by Enhancing ADCC and Activating NK Cell–mediated Inflammation in CLDN18.2-High and -Low Expressing Gastric Cancer Models

  2022cites this paper
• Classic and Current Opinions in Human Organ and Tissue Transplantation

  2022cites this paper
• Impaired intratumoral natural killer cell function in head and neck carcinoma

  2022cites this paper