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Exosomes derived from natural killer cells: transforming immunotherapy for aggressive breast cancer

Alfawaz Altamimi AS, Arockia Babu M, Afzal M, Bishoyi AK, Roopashree R, Saini S, et al.

Med Oncol, 2025 Mar 18;42(4):114.
PMID: 40100465 DOI: 10.1007/s12032-025-02647-y

Natural killer cell-derived exosomes (NK-Exos) hold great promise as immune modulators and immunotherapeutics against cancer due to their intrinsically latent anti-tumor effects. They use these nanosized vesicles to deliver cytotoxic molecules, such as perforin, granzymes, and miRNAs, directly to cancer cells to kill them, avoiding immune suppression. NK-Exos has particular efficacy for treating aggressive breast cancer by modulating the TME to activate the immune response and suppress immunosuppressive factors. Bioengineering advances have extended the therapeutic potential of NK-Exos, which permits precise tumor cell targeting and efficient delivery of therapeutic payloads, including small RNAs and chemotherapeutic agents. In engineered NK-Exos, sensitization of cancer cells to apoptosis, reduction of tumor growth, and resistance to drugs have been demonstrated to be highly effective. When combined, NK-Exos synergizes with radiotherapy, chemotherapy, or checkpoint inhibitors, enhancing therapeutic efficacy, and minimizing systemic toxicity. This review emphasizes the critical role of NK-Exos in breast cancer treatment, their integration into combination therapies, and the need for further research to overcome existing limitations and fully realize their clinical potential.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext Chimeric antigen receptor-natural killer cell therapy: current advancements and strategies to overcome challenges

Kong JC, Sa'ad MA, Vijayan HM, Ravichandran M, Balakrishnan V, Tham SK, et al.

Front Immunol, 2024;15:1384039.
PMID: 38726000 DOI: 10.3389/fimmu.2024.1384039

Chimeric antigen receptor-natural killer (CAR-NK) cell therapy is a novel immunotherapy targeting cancer cells via the generation of chimeric antigen receptors on NK cells which recognize specific cancer antigens. CAR-NK cell therapy is gaining attention nowadays owing to the ability of CAR-NK cells to release potent cytotoxicity against cancer cells without side effects such as cytokine release syndrome (CRS), neurotoxicity and graft-versus-host disease (GvHD). CAR-NK cells do not require antigen priming, thus enabling them to be used as "off-the-shelf" therapy. Nonetheless, CAR-NK cell therapy still possesses several challenges in eliminating cancer cells which reside in hypoxic and immunosuppressive tumor microenvironment. Therefore, this review is envisioned to explore the current advancements and limitations of CAR-NK cell therapy as well as discuss strategies to overcome the challenges faced by CAR-NK cell therapy. This review also aims to dissect the current status of clinical trials on CAR-NK cells and future recommendations for improving the effectiveness and safety of CAR-NK cell therapy.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext Tumour-Associated Macrophages (TAMs) in Colon Cancer and How to Reeducate Them

Yahaya MAF, Lila MAM, Ismail S, Zainol M, Afizan NARNM

J Immunol Res, 2019;2019:2368249.
PMID: 30931335 DOI: 10.1155/2019/2368249

Tumour-associated macrophage (TAM) serves as the site in which most inflammatory cells coreside. It plays an important role in determining the progression and metastasis of a tumour. The characteristic of TAM is largely dependent on the stimuli present in its tumour microenvironment (TME). Under this environment, however, M2 macrophages are found to be in abundance compared to M1 macrophages which later promote tumour progression. Numerous studies have elucidated the relationship between TAM and the progression of tumour; hence, TAM has now been the subject of interest among researchers for anticancer therapy. This review discusses the role of TAM in colorectal cancer (CRC) and some of the potential candidates that could reeducate TAM to fight against CRC. It is with hope that this review will serve as the foundation in understanding TAM in CRC and helping other researchers to select the most suitable candidate to reeducate TAM that could assist in enhancing the tumouricidal activity of M1 macrophage and eventually repress the development of CRC.

Matched MeSH terms: Tumor Microenvironment/immunology*
Fulltext A visualization analysis of immune-related adverse reactions in pulmonary carcinoma

Gong Y, Kang J, Wang M, Firdaus Mohd Hayati M, Wah Goh LP, Bin Syed Abdul Rahim SS

Hum Vaccin Immunother, 2024 Dec 31;20(1):2429237.
PMID: 39588915 DOI: 10.1080/21645515.2024.2429237

Immunotherapy has emerged as a crucial advancement in pulmonary carcinoma treatment. Nevertheless, its unique side effects not only reduce patients' quality of life but also affect treatment efficacy, with severe cases potentially endangering the patient's life. This study uses bibliometric analysis to perform a comprehensive bibliometric analysis literature on IRAEs in lung cancer from 1991 to 2023, retrieved from the Web of Science database. The dataset was analyzed using VOSviewer and CiteSpace to identify trends, key contributors, and emerging research areas. A total of 124 publications were analyzed, revealing a notable increase in research activity post-2015, with China and the USA contributing over 50% of the studies. This research highlights the importance of understanding IRAEs and suggests future investigations into the pulmonary microbiota and tumor microenvironment.

Matched MeSH terms: Tumor Microenvironment/immunology
In human invasive breast ductal carcinoma, tumor stromal macrophages and tumor nest macrophages have distinct relationships with clinicopathological parameters and tumor angiogenesis

Ch'ng ES, Tuan Sharif SE, Jaafar H

Virchows Arch, 2013 Mar;462(3):257-67.
PMID: 23283409 DOI: 10.1007/s00428-012-1362-4

Tumor-associated macrophages play a crucial role in breast cancer progression and tumor angiogenesis. However, evaluation of tumor-associated macrophages incorporating their histological locations is lacking. The aim of this study was to clarify whether macrophages in tumor stroma and macrophages in tumor cell nests have distinctive properties in relation to pertinent breast cancer clinicopathological parameters and tumor angiogenesis. In 94 human invasive breast ductal carcinomas, tumor-associated macrophages were immunostained with anti-CD68 antibody and counted or graded according to these histological locations. Microvessels were immunostained with anti-CD34 antibody and counted for microvessel density. We found that the presence of tumor stromal and tumor nest macrophages was closely correlated (p = 0.001). Both tumor stromal and tumor nest macrophages were associated with mitotic count (p = 0.001 and p = 0.037, respectively). However, only higher tumor stromal macrophage grades were associated with higher tumor grades (p = 0.004) and negative estrogen receptor status (p = 0.007). Multivariate analysis showed that tumors with a high mitotic count score (score 3 vs. scores 1 and 2) had a higher tumor stromal macrophage density (Grades III and IV) when adjusted for tumor size, tubule formation, and estrogen receptor status (odds ratio 3.41, p = 0.010). The tumor nest macrophage count significantly correlated with the microvessel density (p tumor stromal macrophages and tumor nest macrophages residing in different tumor microenvironments have distinctive roles.

Matched MeSH terms: Tumor Microenvironment/immunology
STAT3-related lncRNAs in colorectal cancer progression; Special focus on immune cell's evasion

Saadh MJ, Hamid JA, H M, Kazmi SW, Ahmed MH, Sharma A, et al.

Pathol Res Pract, 2025 Feb;266:155810.
PMID: 39798234 DOI: 10.1016/j.prp.2025.155810

Colorectal cancer (CRC) is globally ranked as the third leading cause of cancer-related deaths in both men and women. There is an urgent need for novel biomarkers to facilitate early diagnosis and enhance patient care, thereby improving treatment response and reducing mortality rates. Signal transducer and activator of transcription 3 (STAT3) is essential for controlling the anti-tumor immune response since it is a hub for several oncogenic signaling pathways. In the tumor environment, STAT3 is widely overactivated in both malignant and non-cancerous cells. It is involved in suppressing the expression of critical immune activation regulators and encouraging the synthesis of immunosuppressive substances. Long noncoding RNAs (lncRNAs), a kind of non-coding RNA, are critical for CRC development, apoptosis, and metastasis because they influence important signaling pathways such as STAT3 signaling and contribute to gene regulation at the epigenetic, transcriptional, and post-transcriptional levels. Moreover, lncRNAs have a significant role in modifying the TME and control the expression of important immunological checkpoints, such as PD-L1. Therefore, a comprehensive understanding of the regulatory roles of lncRNAs is crucial for identifying diagnostic, prognostic, and predictive biomarkers for CRC. Thus, the objective of the present review study is to provide a comprehensive overview of the interaction between the STAT3 signaling pathway and various lncRNAs, as well as their implications for apoptosis, metastasis, and immune evasion in CRC.

Matched MeSH terms: Tumor Microenvironment/immunology
Identification of significant hub genes and pathways associated with metastatic breast cancer and tolerogenic dendritic cell via bioinformatics analysis

Ching KWC, Mokhtar NF, Tye GJ

Comput Biol Med, 2025 Jan;184:109396.
PMID: 39549529 DOI: 10.1016/j.compbiomed.2024.109396

Metastatic breast cancer (MBC) is an advanced-stage breast cancer associated with more than 90 % of cancer-related deaths. Immunosuppressive properties of tolerogenic dendritic cells (tolDCs) in tumour immune microenvironment (TIME) may be a risk factor for the rapid progression to MBC. However, the exact connections between the two are unknown. The aim of the current study is to uncover gene signatures and key pathways associated with MBC and tolDCs via an integrated bioinformatics approach. Gene expression profiles of MBC and tolDCs were retrieved from Gene Expression Omnibus (GEO) to identify common differentially expressed genes (DEGs). From DGE analysis, 529 upregulated common DEGs and 367 downregulated common DEGs had been identified. In enrichment analysis, common DEGs enriched in GO terms of defense response to virus and KEGG pathway of transcriptional misregulation in cancer were reported to be significantly associated with MBC and tolDCs. From the constructed PPI networks, 23 hub genes were identified, although only 5 genes were significant; 3 upregulated (ISG15, OAS2 and RSAD2) and 2 downregulated (eEF2 and PPARG) as they were found to be significantly correlated and had the same expression trend as predicted in validation analysis of overall survival (OS) analysis, expression levels, immune infiltration analysis and immunohistochemistry (IHC) analysis. These 5 hub genes can now be exploited in developing novel therapeutic interventions and as diagnostic biomarkers for enhancing the clinical outcomes of MBC patients.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences

Pan JW, Zabidi MMA, Ng PS, Meng MY, Hasan SN, Sandey B, et al.

Nat Commun, 2020 Dec 22;11(1):6433.
PMID: 33353943 DOI: 10.1038/s41467-020-20173-5

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext Association of BRCA1- and BRCA2-deficiency with mutation burden, expression of PD-L1/PD-1, immune infiltrates, and T cell-inflamed signature in breast cancer

Wen WX, Leong CO

PLoS One, 2019;14(4):e0215381.
PMID: 31022191 DOI: 10.1371/journal.pone.0215381

Immune checkpoint inhibitors have demonstrated effective anti-tumour response in cancer types with high mutation burden (e.g. melanoma) and in subset of cancers with features of genomic instability (e.g. mismatch-repair deficiency). One possible explanation for this effect is the increased expression of immune checkpoint molecules and pre-existing adaptive immune response in these cancers. Given that BRCA1 and BRCA2 are integral in maintaining genomic integrity, we hypothesise that the inactivation of these genes may give rise to breast cancers with such immunogenic phenotype. Therefore, using two large series of publicly available breast cancer datasets, namely that from The Cancer Genome Atlas and Wellcome Trust Institute, we sought to investigate the association between BRCA1- and BRCA2-deficiency with features of genomic instability, expression of PD-L1 and PD-1, landscape of inferred tumour-infiltrating immune cells, and T-cell inflamed signature in breast cancers. Here, we report that BRCA1 and BRCA2-deficient breast cancers were associated with features of genomic instability including increased mutation burden. Interestingly, BRCA1-, but not BRCA2-, deficient breast cancers were associated with increased expression of PD-L1 and PD-1, higher abundance of tumour-infiltrating immune cells, and enrichment of T cell-inflamed signature. The differences in immunophenotype between BRCA1- and BRCA2-deficient breast cancers can be attributed, in part, to PTEN gene mutation. Therefore, features of genomic instability such as that mediated by BRCA1- and BRCA2- deficiency in breast cancer were necessary, but not always sufficient, for yielding T cell-inflamed tumour microenvironment, and by extension, predicting clinical benefit from immunotherapy.

Matched MeSH terms: Tumor Microenvironment/immunology
Fulltext Therapeutic challenges and current immunomodulatory strategies in targeting the immunosuppressive pancreatic tumor microenvironment

Looi CK, Chung FF, Leong CO, Wong SF, Rosli R, Mai CW

J Exp Clin Cancer Res, 2019 Apr 15;38(1):162.
PMID: 30987642 DOI: 10.1186/s13046-019-1153-8

BACKGROUND: Pancreatic cancer is one of the most lethal type of cancers, with an overall five-year survival rate of less than 5%. It is usually diagnosed at an advanced stage with limited therapeutic options. To date, no effective treatment options have demonstrated long-term benefits in advanced pancreatic cancer patients. Compared with other cancers, pancreatic cancer exhibits remarkable resistance to conventional therapy and possesses a highly immunosuppressive tumor microenvironment (TME).
MAIN BODY: In this review, we summarized the evidence and unique properties of TME in pancreatic cancer that may contribute to its resistance towards immunotherapies as well as strategies to overcome those barriers. We reviewed the current strategies and future perspectives of combination therapies that (1) promote T cell priming through tumor associated antigen presentation; (2) inhibit tumor immunosuppressive environment; and (3) break-down the desmoplastic barrier which improves tumor infiltrating lymphocytes entry into the TME.
CONCLUSIONS: It is imperative for clinicians and scientists to understand tumor immunology, identify novel biomarkers, and optimize the position of immunotherapy in therapeutic sequence, in order to improve pancreatic cancer clinical trial outcomes. Our collaborative efforts in targeting pancreatic TME will be the mainstay of achieving better clinical prognosis among pancreatic cancer patients. Ultimately, pancreatic cancer will be a treatable medical condition instead of a death sentence for a patient.

Matched MeSH terms: Tumor Microenvironment/immunology*

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