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Natural killer (NK) cells are critical to the innate immune system, as they recognize antigens without prior sensitization, and contribute to the control and clearance of viral infections and cancer. However, a significant proportion of NK cells in mice and humans do not express classical inhibitory receptors during their education process and are rendered naturally "anergic", i.e., exhibiting reduced effector functions. The molecular events leading to NK cell anergy as well as their relation to those underlying NK cell exhaustion that arises from overstimulation in chronic conditions, remain unknown. Here, we characterize the "anergic" phenotype and demonstrate functional, transcriptional, and phenotypic similarities to the "exhausted" state in tumor-infiltrating NK cells. Furthermore, we identify zinc finger transcription factor Egr2 and diacylglycerol kinase DGKα as common negative regulators controlling NK cell dysfunction. Finally, experiments in a 3D organotypic spheroid culture model and an in vivo tumor model suggest that a nanoparticle-based delivery platform can reprogram these dysfunctional natural killer cell populations in their native microenvironment. This approach may become clinically relevant for the development of novel anti-tumor immunotherapeutic strategies. Synopsis: The mechanisms underlying naturally occurring "anergic" and overstimulation-induced "exhausted" states of natural killer (NK) cells remain unclear. This study identifies common functional and phenotypic characteristics of these two dysfunctional states, and identifies common regulators that can be targeted to reprogram dysfunctional NK cells. The transcription factor Egr2 and diacylglycerol kinase DGKα regulate both dysfunctional states of NK cells. Egr2 silencing rescues anergic NK cell cytotoxicity via the EGR2-DGKα-MAPK-pERK axis, potentially modulating SHP-1 activity and calcium levels. Naturally occurring anergic NK cells have functional, transcriptional, and phenotypic similarities to exhausted NK cells within the tumor microenvironment. A nanoparticle-based method can reprogram dysfunctional NK cells in their native milieu and increase their anti-tumor activity. Common intrinsic regulators of dysfunctional "anergic" and "exhausted" NK cells can be targeted to restore cytotoxicity. [ABSTRACT FROM AUTHOR]

Radiotherapy, as one of the most common strategies for clinical cancer treatment, suffers from failure due to the hypoxia, inflammation, and radiosensitivity difference of malignant tumors, side effects, and radioresistance. Heterojunction‐based radiosensitizers attract great attention to the lower excitation energy and remarkable catalytic activity as compared to typical transition metal radiosensitizers. However, the bio‐application of heterojunction radiosensitizers is in its infancy due to the challenges in structure engineering, rational energy band alignment, and ideal photogenerated carrier migration. Herein, a bimetallic metal‐organic framework (MOF)‐based heterojunction radiosensitizer is reasonably designed to enhance the radiodynamic therapeutic efficiency of Ru complex, and to activate natural killer (NK) cell‐mediated innate immune responses for promoted tumor immunotherapy. This study not only designs a novel bimetallic MOF‐based heterojunction structure but also elucidates the underlying action mechanisms in inhibiting cancer proliferation, which sheds light on the practicable design of radiosensitizers and the tumor combination treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of novel cancer treatment techniques is essential because malignant tumors represent a severe threat to human life and health. By inhibiting immunological sites and chimeric antigen receptors, tumor immunotherapy is becoming more and more significant. There are several immune cells linked to tumors, and NK cells are one type that is being utilized more and more in therapeutic settings because of the inherent benefits. Additionally, the anti-tumor immune response and NK cell-tracking ability are improved by the use of nanomaterials. In order to accomplish the combined application of NK cells and nanomaterials, this review will concentrate on the immunological application and imaging study of nanoparticles on NK cells. The prognosis for cancer patients has declined dramatically in recent years due to the challenges in treating malignant tumors. Tumor immunotherapy, which includes immune target inhibition and chimeric antigen receptor cell treatment, is currently evolving quickly. Among them, natural killer (NK) cells are gradually becoming another preferred cell immunotherapy after T cell immunotherapy due to their unique killing effects in innate and adaptive immunity. NK cell therapy has shown encouraging outcomes in clinical studies; however, there are still some problems, including limited efficacy in solid tumors, inadequate NK cell penetration, and expensive treatment expenses. Noteworthy benefits of nanomaterials include their chemical specificity, biocompatibility, and ease of manufacturing; these make them promising instruments for enhancing NK cell anti-tumor immune responses. Nanomaterials can promote NK cell homing and infiltration, participate in NK cell modification and non-invasive cell tracking and imaging modes, and greatly increase the effectiveness of NK cell immunotherapy. The introduction of NK cell-based immunotherapy research and a more detailed discussion of nanomaterial research in NK cell-based immunotherapy and molecular imaging will be the main topics of this review. [ABSTRACT FROM AUTHOR]

The prognosis for cancer patients has declined dramatically in recent years due to the challenges in treating malignant tumors. Tumor immunotherapy, which includes immune target inhibition and chimeric antigen receptor cell treatment, is currently evolving quickly. Among them, natural killer (NK) cells are gradually becoming another preferred cell immunotherapy after T cell immunotherapy due to their unique killing effects in innate and adaptive immunity. NK cell therapy has shown encouraging outcomes in clinical studies; however, there are still some problems, including limited efficacy in solid tumors, inadequate NK cell penetration, and expensive treatment expenses. Noteworthy benefits of nanomaterials include their chemical specificity, biocompatibility, and ease of manufacturing; these make them promising instruments for enhancing NK cell anti-tumor immune responses. Nanomaterials can promote NK cell homing and infiltration, participate in NK cell modification and non-invasive cell tracking and imaging modes, and greatly increase the effectiveness of NK cell immunotherapy. The introduction of NK cell-based immunotherapy research and a more detailed discussion of nanomaterial research in NK cell-based immunotherapy and molecular imaging will be the main topics of this review.

Background: Colorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC. Methods: NK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity. Results: HLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control. Conclusions: Our results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy. [ABSTRACT FROM AUTHOR]

BackgroundColorectal cancer (CRC) is a heterogeneous disease with variable mutational profile and tumour microenvironment composition that influence tumour progression and response to treatment. While chemoresistant and poorly immunogenic CRC remains a challenge, the development of new strategies guided by biomarkers could help stratify and treat patients. Allogeneic NK cell transfer emerges as an alternative against chemoresistant and poorly immunogenic CRC.MethodsNK cell-related immunological markers were analysed by transcriptomics and immunohistochemistry in human CRC samples and correlated with tumour progression and overall survival. The anti-tumour ability of expanded allogeneic NK cells using a protocol combining cytokines and feeder cells was analysed in vitro and in vivo and correlated with CRC mutational status and the expression of ligands for immune checkpoint (IC) receptors regulating NK cell activity.ResultsHLA-I downmodulation and NK cell infiltration correlated with better overall survival in patients with a low-stage (II) microsatellite instability-high (MSI-H) CRC, suggesting a role of HLA-I as a prognosis biomarker and a potential benefit of NK cell immunotherapy. Activated allogeneic NK cells were able to eliminate CRC cultures without PD-1 and TIM-3 restriction but were affected by HLA-I expression. In vivo experiments confirmed the efficacy of the therapy against both HLA+ and HLA− CRC cell lines. Concomitant administration of pembrolizumab failed to improve tumour control.ConclusionsOur results reveal an immunological profile of CRC tumours in which immunogenicity (MSI-H) and immune evasion mechanisms (HLA downmodulation) favour NK cell immunosurveillance at early disease stages. Accordingly, we have shown that allogeneic NK cell therapy can target tumours expressing mutations conferring poor prognosis regardless of the expression of T cell-related inhibitory IC ligands. Overall, this study provides a rationale for a new potential basis for CRC stratification and NK cell-based therapy.

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1. [ABSTRACT FROM AUTHOR]

The endoplasmic reticulum aminopeptidase ERAP1 regulates innate and adaptive immune responses by trimming peptides for presentation by major histocompatibility complex (MHC) class I molecules. Previously, we have shown that genetic or pharmacological inhibition of ERAP1 on murine and human tumor cell lines perturbs the engagement of NK cell inhibitory receptors Ly49C/I and Killer-cell Immunoglobulin-like receptors (KIRs), respectively, by their specific ligands (MHC class I molecules), thus leading to NK cell killing. However, the effect of ERAP1 inhibition in tumor cells was highly variable, suggesting that its efficacy may depend on several factors, including MHC class I typing. To identify MHC class I alleles and KIRs that are more sensitive to ERAP1 depletion, we stably silenced ERAP1 expression in human HLA class I-negative B lymphoblastoid cell line 721.221 (referred to as 221) transfected with a panel of KIR ligands (i.e. HLA-B*51:01, -Cw3, -Cw4 and -Cw7), or HLA-A2 which does not bind any KIR, and tested their ability to induce NK cell degranulation and cytotoxicity. No change in HLA class I surface expression was detected in all 221 transfectant cells after ERAP1 depletion. In contrast, CD107a expression levels were significantly increased on NK cells stimulated with 221-B*51:01 cells lacking ERAP1, particularly in the KIR3DL1-positive NK cell subset. Consistently, genetic or pharmacological inhibition of ERAP1 impaired the recognition of HLA-B*51:01 by the YTS NK cell overexpressing KIR3DL1*001, suggesting that ERAP1 inhibition renders HLA-B*51:01 molecules less eligible for binding to KIR3DL1. Overall, these results identify HLA-B*51:01/KIR3DL1 as one of the most susceptible combinations for ERAP1 inhibition, suggesting that individuals carrying HLA-B*51:01-like antigens may be candidates for immunotherapy based on pharmacological inhibition of ERAP1.

Relapse is the major cause of failure of high-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) for B cell non-Hodgkin lymphomas (B-NHL). Improvement strategies include use in combination with effective immunotherapies. We hypothesized that the combination of rituximab/HDC/ASCT with expanded cord blood (CB)-derived natural killer (NK) cells is safe and active in B-NHL. Patients with B-NHL age 15 to 70 years and appropriate ASCT candidates were eligible for the study. The CB units were selected without considering HLA match with the recipient. The CB NK cells were expanded from day -19 to day -5. Treatment included rituximab on days -13 and -7, BEAM (carmustine/etoposide/cytarabine/melphalan) on days -13 to -7, lenalidomide on days -7 to -2, CB NK infusion (10 8 /kg) on day -5, and ASCT (day 0). The primary endpoint was 30-day treatment-related mortality (TRM); secondary endpoints included relapse-free survival (RFS), overall survival (OS), and persistence of CB NK cells. We enrolled 20 patients. CB NK cells were expanded a median of 1552-fold with >98% purity and >96% viability. We saw no adverse events attributable to the CB NK cells and 0% 30-day TRM. At median follow-up of 47 months, the RFS and OS rates were 53% and 74%, respectively. CB NK cells were detectable in blood for 2 weeks, independent of HLA-mismatch status. CD16 expression in donor NK cells was correlated favorably with outcome, and homozygosity for the high-affinity CD16 variant (158 V/V) in CB, but not recipient, NK cells was correlated with better outcomes. Our data indicate that the combination of expanded and highly purified CB-derived NK cells with HDC/ASCT for B-NHL is safe. CD16 expression in donor NK cells, particularly if homozygous for the high-affinity CD16 variant, was correlated with better outcomes., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based therapies are undergoing clinical trials and show considerable effectiveness for hematological tumors. In these types of cancers, the immune cells themselves often undergo malignant transformation, which determines the features of the disease. In contrast, the current use of NK cells as therapeutic agents for the treatment of solid tumors is much less promising. Most studies are at the stage of preclinical investigation, but few progress to clinical trials. Low efficiency of NK cell migration and functional activity in the tumor environment are currently considered the major barriers to NK cell anti-tumor therapies. Various therapeutic combinations, genetic engineering methods, alternative sources for obtaining NK cells, and other techniques are aiming at the development of promising NK cell anticancer therapies, regardless of tumorigenesis. In this review, we compare the role of NK cells in the pathogenesis of hematological and solid tumors and discuss current prospects of NK-cell-based therapy for hematological and solid tumors.

For more than a decade, investigators have pursued methods to genetically engineer NK cells for use in clinical therapy against cancer. Despite considerable advances in viral transduction of hematopoietic stem cells and T cells, transduction efficiencies for NK cells have remained disappointingly low. Here we show that NK cells can be efficiently genetically reprogrammed using a cGMP-compliant mRNA electroporation method that induces rapid and reproducible transgene expression in nearly all transfected cells, without negatively influencing their viability, phenotype and cytotoxic function. To study its potential therapeutic application, we used this approach to improve key aspects involved in efficient lymphoma targeting by adoptively infused ex vivo expanded NK cells. Electroporation of NK cells with mRNA coding for the chemokine receptor CCR7 significantly promoted migration towards the lymph node-associated chemokine CCL19. Further, introduction of mRNA coding for the high-affinity antibody-binding receptor CD16 (CD16-158V) substantially augmented NK cell cytotoxicity against rituximab-coated lymphoma cells. Based on these data, we conclude this approach can be utilized to genetically modify multiple modalities of NK cells in a highly efficient manner with the potential to improve multiple facets of their in vivo tumor targeting, opening a new arena for the development of more efficacious adoptive NK cell-based cancer immunotherapies.

Tumor immunotherapy has been an important advancement in cancer treatment in recent years. Compared with T cell-based therapy, natural killer (NK) cell-based therapy does not require human leukocyte antigen matching and has fewer side effects; thus, NK cell therapy has gradually attracted the attention of researchers and clinicians. Reliable and effective animal models are essential for evaluating the effects of NK cell therapy. NK cells kill cancer cells mainly through apoptosis. In this study, we first established a 3D coculture model using fluorescence resonance energy transfer (FRET)-based lung or breast cancer cells and tdTomato-labeled NK cells. We observed that cancer cells changed from green to blue when undergoing apoptosis induced by red NK cells. We then coinjected these green cancer cells with red NK cells into zebrafish to visualize the interaction between them and the killing process of NK cells against cancer cells in real-time and at single-cell resolution in circulation. Using this model, we found that NK cells can quickly kill cancer cells in zebrafish circulation in 40 min and the caspase-3 can be activated in 5–10 min. This FRET-based zebrafish tumor model can serve as a powerful in vivo tool that can facilitate the development of NK cell-based therapy. More importantly, cancer cells from cancer patients can be labeled with our apoptotic biosensor and then transplanted into zebrafish to evaluate the sensitivity of the cancer cells to NK cells to help clinicians make treatment plans that can benefit patients. [ABSTRACT FROM AUTHOR]

For more than a decade, investigators have pursued methods to genetically engineer natural killer (NK) cells for use in clinical therapy against cancer. Despite considerable advances in viral transduction of hematopoietic stem cells and T cells, transduction efficiencies for NK cells have remained disappointingly low. Here, we show that NK cells can be genetically reprogramed efficiently using a cGMP-compliant mRNA electroporation method that induces rapid and reproducible transgene expression in nearly all transfected cells, without negatively influencing their viability, phenotype, and cytotoxic function. To study its potential therapeutic application, we used this approach to improve key aspects involved in efficient lymphoma targeting by adoptively infused ex vivo-expanded NK cells. Electroporation of NK cells with mRNA coding for the chemokine receptor CCR7 significantly promoted migration toward the lymph node-associated chemokine CCL19. Further, introduction of mRNA coding for the high-affinity antibody-binding receptor CD16 (CD16-158V) substantially augmented NK cell cytotoxicity against rituximab- coated lymphoma cells. Based on these data, we conclude that this approach can be utilized to genetically modify multiple modalities of NK cells in a highly efficient manner with the potential to improve multiple facets of their in vivo tumor targeting, thus, opening a new arena for the development of more efficacious adoptive NK cell-based cancer immunotherapies. [ABSTRACT FROM AUTHOR]

[Display omitted] • BCL2 inhibitor venetoclax can enhance the efficacy of NK cells against AML. • The synergistic effect of combining venetoclax with NK cells resulted from the NKG2D/NKG2DL immune ligand receptor pathway activated by venetoclax. • NFKB signaling pathway involved in venetoclax-induced NKG2DL expression. Venetoclax, a selective B-cell lymphoma-2 (BCL2) inhibitor, has a potential therapeutic effect when combined with demethylating agents in the first-line setting of unfit elderly patients with acute myeloid leukaemia (AML); however, efficacy is still limited in refractory/recurrent AML. Therefore, exploration of a suitable novel treatment scheme is urgently needed.However, combining venetoclax with NK cell-based immunotherapy has not been studied. The cytotoxicity of NK cell combined with venetoclax was assessed in vitro using flow cytometry. Venetoclax-induced natural killer group 2 member D (NKG2D) ligand (NKG2DL) expression was detected by flow cytometry and western blotting. Mechanisms underlying venetoclax-induced NKG2DL expression were found by GSE127200 analysis and investigated using real-time PCR (Q-PCR) and western blotting. Flow cytometric analysis showed that combining venetoclax with NK cells produced synergistic anti-leukaemia effects similar to those of venetoclax + azacitidine. Venetoclax could render AML cell lines and primary AML cells sensitive to NK cell killing by promoting NK cell degranulation, NK-AML cell recognition and NK cell secretion of interferon (IFN)-γ and granzyme B. The synergistic effect resulted from venetoclax-induced NKG2DL upregulation in AML cells and could be undermined by blocking NKG2D on NK cells. This finding suggests that venetoclax enhances NK cell killing activity by activating the NKG2D/NKG2DL ligand–receptor pathway. Furthermore, the nuclear factor-kappa-B (NFKB) signalling pathway was involved in venetoclax-induced NKG2DL upregulation. Collectively, our data confirm that venetoclax combined with NK cells induces synergistic AML cell cytolysis and preliminarily revealed that venetoclax could selectively induce NKG2DLs on AML cells via NFKB signalling pathway. [ABSTRACT FROM AUTHOR]

NK cells are an attractive target for cancer immunotherapy due to their potent antitumor activity. The main advantage of using NK cells as cytotoxic effectors over T cells is a reduced risk of graft versus host disease. At present, several variants of NK-cell-based therapies are undergoing clinical trials and show considerable effectiveness for hematological tumors. In these types of cancers, the immune cells themselves often undergo malignant transformation, which determines the features of the disease. In contrast, the current use of NK cells as therapeutic agents for the treatment of solid tumors is much less promising. Most studies are at the stage of preclinical investigation, but few progress to clinical trials. Low efficiency of NK cell migration and functional activity in the tumor environment are currently considered the major barriers to NK cell anti-tumor therapies. Various therapeutic combinations, genetic engineering methods, alternative sources for obtaining NK cells, and other techniques are aiming at the development of promising NK cell anticancer therapies, regardless of tumorigenesis. In this review, we compare the role of NK cells in the pathogenesis of hematological and solid tumors and discuss current prospects of NK-cell-based therapy for hematological and solid tumors. [ABSTRACT FROM AUTHOR]

Simple Summary: Natural Killer cells have shown promise to treat different malignancies. Several methods have been described to obtain fully activated NK cells for clinical use. Here, we use different cell culture media and different artificial antigen presenting cells to optimize a GMP compliant manufacturing method to obtain activated and expanded NK cells suitable for clinical use. Natural killer (NK) cells represent promising tools for cancer immunotherapy. We report the optimization of an NK cell activation–expansion process and its validation on clinical-scale. Methods: RPMI-1640, stem cell growth medium (SCGM), NK MACS and TexMACS were used as culture mediums. Activated and expanded NK cells (NKAE) were obtained by coculturing total peripheral blood mononuclear cells (PBMC) or CD45RA+ cells with irradiated K562mbIL15-41BBL or K562mbIL21-41BBL. Fold increase, NK cell purity, activation status, cytotoxicity and transcriptome profile were analyzed. Clinical-grade NKAE cells were manufactured in CliniMACS Prodigy. Results: NK MACS and TexMACs achieved the highest NK cell purity and lowest T cell contamination. Obtaining NKAE cells from CD45RA+ cells was feasible although PBMC yielded higher total cell numbers and NK cell purity than CD45RA+ cells. The highest fold expansion and NK purity were achieved by using PBMC and K562mbIL21-41BBL cells. However, no differences in activation and cytotoxicity were found when using either NK cell source or activating cell line. Transcriptome profile showed to be different between basal NK cells and NKAE cells expanded with K562mbIL21-41BBL or K562mbIL15-41BBL. Clinical-grade manufactured NKAE cells complied with the specifications from the Spanish Regulatory Agency. Conclusions: GMP-grade NK cells for clinical use can be obtained by using different starting cells and aAPC. [ABSTRACT FROM AUTHOR]

Recent advances in cancer immunotherapy have exploited the efficient potential of natural killer (NK) cells to kill tumor cells through antibody-dependent cell-mediated cytotoxicity (ADCC). However, this therapeutic strategy is seriously limited by tumor antigen heterogeneity since antibodies can only recognize specific antigens. In this work, modified antibodies or their Fc fragments that can target solid tumors without the necessity of specific antigen presentation on tumors are developed. Briefly, Fc fragments or therapeutic monoclonal antibodies are conjugated with the N-terminus of pH low insertion peptide so that they will selectively assemble onto the membrane of solid tumor cells via the conformational transformation of the peptide by responding to the acidic tumor microenvironment. The inserted Fc fragments or antibodies can efficiently activate NK cells, initiating ADCC and killing multiple types of tumor cells, including antigen-negative cancer cells. In vivo therapeutic results also exhibit significant efficacy on both primary solid tumors and tumor metastasis. These modified Fc fragments and antibodies present strong potential to overcome the limitation of tumor antigen heterogeneity, broadening the applications of NK cell immunotherapy on solid tumor treatment., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)