Sex disparities revealed by single-cell and bulk sequencing and their impacts on the efficacy of immunotherapy in esophageal cancer.
Biology of sex differences
BACKGROUND:There is an ongoing debate on whether sex affects immune-suppressive tumor microenvironment and immunotherapy. Here, we explored the underlying molecular bases for sex dimorphisms and their impact on the efficacy of immunotherapy in esophageal cancer (EC). METHODS:2360 EC patients from phase 3 trials were pooled to compare overall survivals by calculating hazard ratios (HRs) and their 95% confidence intervals (CIs). Genomic data of 1425 samples were integrated to depict the genomic landscapes and antigenic features. We also examined the sex disparities based on single-cell RNA sequencing and T cell receptor-sequencing data from 105,145 immune cells in 60 patients. RESULTS:Immunotherapy was associated with favorable outcomes in men (HR, 0.71; 95% CI, 0.65-0.79; P < 0.001), but not in women (HR, 0.98; 95% CI, 0.78-1.23; P = 0.84) (P =0.02). The frequencies of 8 gene mutations, 12 single base substitutions signatures, and 131 reactome pathways were significantly different between male and female. Additionally, six subtypes of HLA-II antigens were enriched in women. Hence, we constructed and then validated a sex-related signature to better predict the outcomes of immunotherapy. Exhausted CD8 T cells were highly infiltrated in men, while naïve CD8 T cells were more common in women. Further examinations on multiple malignancies suggested exhausted CD8 T cells were enriched in patients who responded to immunotherapy. CONCLUSIONS:Our study delineated the robust genomic and cellular sex disparities in EC. Furthermore, male, rather than female, derived significantly benefits from immunotherapy. These results have implications for treatment decision-making and developing immunotherapy for personalized care. In the past several years, immunotherapy has gradually replaced the traditional chemotherapy as the standard treatment in esophageal cancer. It is well-established that immunological responses in male and female differ significantly. However, there is an ongoing debate on whether sex can impact the treatment outcomes in immunotherapy. In the present study, we systematically characterized the genomic and cellular landscapes of esophageal cancer, and revealed the significant differences between male and female patients. Furthermore, with over 2000 patients with esophageal cancer, we showed that only men can benefit from immunotherapy. In women, immunotherapy failed to show superior over chemotherapy. These results have implications for treatment decision-making and developing next-generation immunotherapy for personalized care.
10.1186/s13293-024-00598-z
Efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy in esophageal cancer: A systematic review and meta-analysis.
Frontiers in immunology
Background:Significant progress has been made in the investigation of neoadjuvant immune-chemoradiotherapy (NICRT) and neoadjuvant immune-chemotherapy (NICT) on the outcomes of esophageal cancer patients. To summarize the current developments, a systematic review and meta-analysis were conducted to evaluate the efficacy and safety of neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy. Methods:A search strategy of prospective studies on esophageal cancer receiving neoadjuvant immunotherapy was predefined to scan PubMed, Embase, Cochrane, and additional major conferences for prospective studies. Efficacy was assessed by pathological complete response (pCR), major pathological response (MPR), and R0 resection rates. Safety was evaluated based on the incidence of grade ≥ 3 treatment-related adverse events (TRAEs), neoadjuvant therapy completion rate, surgical resection rate, and surgical delay rate. Differences between the NICRT and NICT groups were also analyzed. Results:A total of 38 studies qualified for the analysis. The pooled pCR, MPR, and R0 resection rates were 30, 58, and 99%, respectively. The pCR and MPR in the NICRT vs. NICT group were 38% vs. 28% (p=0.078) and 67% vs. 57% (p=0.181), respectively. The pooled incidence of grade ≥ 3 TRAEs was 24% (NICRT,58%, I = 61% vs. NICT,18%, I = 79%; p<0.001). In addition, the pooled neoadjuvant therapy completion and surgical resection rates were 92% and 85%, respectively; the difference was not statistically significant between the NICRT and NICT groups. Conclusions:Neoadjuvant immunotherapy combined with chemoradiotherapy or chemotherapy is effective and safe in the short term for locally advanced esophageal cancer. However, further randomized trials are needed to confirm which combined model is more favorable. Systematic review registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021284266, identifier CRD42021284266.
10.3389/fimmu.2023.1117448
Efficacy and safety of immunochemotherapy, immunotherapy, chemotherapy, and targeted therapy as first-line treatment for advanced and metastatic esophageal cancer: a systematic review and network meta-analysis.
The Lancet regional health. Western Pacific
Background:The treatment of esophageal cancer has entered a new phase with the development of immunotherapy. The current investigation purpose is to investigate and contrast the efficacy and safety of immunotherapy, immunochemotherapy, chemotherapy, and targeted therapy as first-line treatment for individuals suffering from advanced and metastatic esophageal cancer. Methods:Within the framework of this systematic review and network meta-analysis, clinical trials published or reported in English up until 01 May, 2022, were retrieved from Embase, PubMed, Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov databases, ESMO, and ASCO. The analysis incorporated randomized controlled trials (RCTs) from phase 2 to 3 that evaluated a minimum of two first-line therapeutic regimens for metastatic esophageal cancer were included in the analysis. The primary outcomes were overall survival (OS) and progression-free survival (PFS). Secondary clinical outcomes included the incidence of objective response rate (ORR), and adverse events (AEs) of any grade and ≥3 grade. Relative summary data were extracted from included studies by GZ, HS, WS, and TD. For clear statistical analysis, chemotherapy was divided into two categories of fluorouracil-based chemotherapy (FbCT) and fluorouracil-free chemotherapy (FfCT). Bayesian frequentist approach was employed to conduct the network meta-analysis. The indirect intercomparison between regimens was presented with league tables (HRs and 95% CI for OS and PFS, ORs and 95% CI for ORR and AEs). A greater surface value under the cumulative ranking (SUCRA) indicates a higher potential ranking for the corresponding treatment. A further calculation of relative results about esophageal squamous cell cancer was performed in the subgroup analysis. The current protocol for the systematic review has been properly registered on PROSPERO (registration number: CRD42021241145). Findings:The final analysis comprised 17 trials that involved 9128 patients and 19 distinct treatment regimens. Within the scope of investigated immunotherapy (IO) combinations, toripalimab + FfCT (tori + FfCT) demonstrated the best OS advantages (tori + FfCT vs. FbCT, HR 0.57, 95% CI 0.38-0.85; tori + FfCT vs. FfCT, HR 0.58, 95% CI 0.43-0.78). In terms of PFS, camrelizumab + FfCT (cam + FfCT) demonstrated the best PFS advantages (FbCT vs. cam + FfCT, HR 1.79, 95% CI 1.22-2.63; FfCT vs. cam + FfCT, HR 1.79, 95% CI 1.47-2.17). Nivolumab + FbCT (nivo + FbCT vs. FfCT, OR 3.29, 95% CI 1.43-7.56) showed the best objective responses. Compared to the conventional chemotherapy regimen, the toxicity was observed to be the slightest for the tori + FfCT (FbCT vs. tori + FfCT, OR 3.07, 95% CI 1.22-7.7) and sintilimab + FfCT (FbCT vs. sin + FfCT, OR 2.93, 95% CI 1.16-7.37). The results in this study were evaluated as having a low heterogeneity since the I value was ≤25% in all analyses. Interpretation:Compared to foreign IO combinations, sin + FfCT, tori + FfCT, cam + FfCT, and tisle + FbCT are superior first-line treatment options for patients with advanced and metastatic esophageal cancer. Although foreign IO combinations, such as pembro + FbCT and nivo + FbCT obtained better objective response rates than other IO combinations, the addition of chemotherapy to IO worsens the safety profiles. Our findings could provide complementary evidence for current guideline recommendations. Funding:This work was supported by a grant from the Science and Technology Program of Guangzhou, China (202206010103); and Natural Science Foundation of Guangdong Province (2022A1515012469).
10.1016/j.lanwpc.2023.100841
Advancing Esophageal Cancer Treatment: Immunotherapy in Neoadjuvant and Adjuvant Settings.
Cancers
Locally advanced esophageal cancer (LAEC) poses a significant and persistent challenge in terms of effective treatment. Traditionally, the primary strategy for managing LAEC has involved concurrent neoadjuvant chemoradiation followed by surgery. However, achieving a pathologic complete response (pCR) has proven to be inconsistent, and despite treatment, roughly half of patients experience locoregional recurrence or metastasis. Consequently, there has been a paradigm shift towards exploring the potential of immunotherapy in reshaping the landscape of LAEC management. Recent research has particularly focused on immune checkpoint inhibitors, investigating their application in both neoadjuvant and adjuvant settings. These inhibitors, designed to block specific proteins in immune cells, are meant to enhance the immune system's ability to target and combat cancer cells. Emerging evidence from these studies suggests the possibility of a mortality benefit, indicating that immunotherapy may contribute to improved overall survival rates for individuals grappling with esophageal cancer. This manuscript aims to meticulously review the existing literature surrounding neoadjuvant and adjuvant immunotherapy in the context of LAEC management. The intention is to thoroughly examine the methodologies and findings of relevant studies, providing a comprehensive synthesis of the current understanding of the impact of immunotherapy on esophageal cancer.
10.3390/cancers16020318
Biomarkers for immunotherapy in esophageal cancer.
Frontiers in immunology
The development of immunotherapy, especially immune-checkpoint inhibitors targeting PD-1/PD-L1, has improved the outcomes of patients with esophageal cancer. However, not all population derives benefit from the agents. Recently, kinds of biomarkers were introduced to predict the response to immunotherapy. However, the effects of these reported biomarkers are controversial and many challenges remain. In this review, we aim to summarize the current clinical evidence and provide a comprehensive understanding of the reported biomarkers. We also discuss the limits of the present biomarkers and propose our own opinions on which viewers' discretion are advised.
10.3389/fimmu.2023.1117523
Current state of the art: immunotherapy in esophageal cancer and gastroesophageal junction cancer.
Cancer immunology, immunotherapy : CII
Esophageal cancers have a high mortality rate and limited treatment options especially in the advanced/metastatic setting. Squamous cell carcinoma (SCC) and adenocarcinoma are two distinct types of esophageal cancer. Esophageal SCC is more common in nonindustrialized countries with risk factors including smoking, alcohol use, and achalasia. Adenocarcinoma is the predominant esophageal cancer in developed nations, and risk factors include chronic gastroesophageal reflux disease, obesity, and smoking. Chemotherapy has been the mainstay of therapy for decades until immunotherapy made its debut in the past few years. Immune checkpoint inhibitors have been tested in many studies now and are becoming an essential component of esophageal cancer treatment. Monoclonal antibodies that selectively inhibit programmed cell death-1 (PD-1) activity such as pembrolizumab and nivolumab, have become standard of care in the treatment of esophageal cancer. Several other anti-PD-1 antibodies like camrelizumab, toripalimab, sintilimab, trislelizumab are under investigation in different stages of clinical trials. Here we provide a comprehensive review of extant literature as well as ongoing trials with various combinations of chemotherapy or other targeted therapy with a focus on different histological subgroups of esophageal cancer and in different clinical settings.
10.1007/s00262-023-03566-5
Advances in targeted therapy and immunotherapy for esophageal cancer.
Chinese medical journal
ABSTRACT:Esophageal cancer (EC) is one of the most common aggressive malignant tumors in the digestive system with a severe epidemiological situation and poor prognosis. The early diagnostic rate of EC is low, and most EC patients are diagnosed at an advanced stage. Multiple multimodality treatments have gradually evolved into the main treatment for advanced EC, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. And the emergence of targeted therapy and immunotherapy has greatly improved the survival of EC patients. This review highlights the latest advances in targeted therapy and immunotherapy for EC, discusses the efficacy and safety of relevant drugs, summarizes related important clinical trials, and tries to provide references for therapeutic strategy of EC.
10.1097/CM9.0000000000002768
From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer.
Vrána David,Matzenauer Marcel,Neoral Čestmír,Aujeský René,Vrba Radek,Melichar Bohuslav,Rušarová Nikol,Bartoušková Marie,Jankowski Janusz
International journal of molecular sciences
Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.
10.3390/ijms20010013
Prognostic and predictive value of angiogenesis-associated serum proteins for immunotherapy in esophageal cancer.
Journal for immunotherapy of cancer
BACKGROUND:Immune checkpoint inhibitors (ICIs) have significantly improved patient survival in multiple cancers. However, therapy response in esophageal cancer is limited to subgroups of patients and clinically useful predictive biomarkers are lacking. METHODS:We collected a series of plasma samples from 91 patients with esophageal cancer before and after ICI treatment. The Olink Immuno-Oncology panel (92 proteins) with proximity extension assays was used to detect the dynamic changes in plasma and potential biomarkers associated with treatment outcomes. We screened all survival-related proteins and established a risk score model to better predict the prognosis and treatment response in patients with esophageal cancer immunotherapy. RESULTS:We found that 47 out of 92 quantified proteins had significant changes in plasma levels during ICI treatment (p<0.050), and these changed proteins were involved in immune-related reactions, such as intercellular adhesion and T-cell activation. Notably, the baseline levels of three angiogenesis-related proteins (IL-8, TIE2, and HGF) were significantly associated with the survival outcomes of patients treated with ICIs (p<0.050). According to these prognostic proteins, we established an angiogenesis-related risk score, which could be a superior biomarker for ICI response prediction. In addition, antiangiogenic therapy combined with ICIs significantly improved overall survival compared with ICI monotherapy (p=0.044). CONCLUSIONS:An angiogenesis-related risk score based on three proteins (IL-8, TIE2, and HGF) could predict ICI response and prognosis in patients with esophageal cancer, which warrants verification in the future. Our study highlights the potential application of combining ICIs and antiangiogenic therapy and supports Olink plasma protein sequencing as a liquid biopsy method for biomarker exploration.
10.1136/jitc-2022-006616
Neoadjuvant immunotherapy for resectable esophageal cancer: A review.
Frontiers in immunology
Esophageal cancer (EC) is one of the most common cancers worldwide, especially in China. Despite therapeutic advances, the 5-year survival rate of EC is still dismal. For patients with resectable disease, neoadjuvant chemoradiotherapy (nCRT) in combination with esophagectomy is the mainstay of treatment. However, the pathological complete response (pCR) rate to nCRT of 29.2% to 43.2% is not satisfactory, and approximately half of the patients will develop either a locoregional recurrence or distant metastasis. It is, therefore, necessary to explore novel and effective treatment strategies to improve the clinical efficacy of treatment. Immunotherapy utilizing immune checkpoint inhibitors (ICIs) has significantly changed the treatment paradigm for a wide variety of advanced cancers, including EC. More recently, increasing clinical evidence has demonstrated that neoadjuvant immunotherapy can potentially improve the survival of patients with resectable cancers. Furthermore, accumulating findings support the idea that chemotherapy and/or radiotherapy can activate the immune system through a variety of mechanisms, so a combination of chemotherapy and/or radiotherapy with immunotherapy can have a synergistic antitumor effect. Therefore, it is reasonable to evaluate the role of neoadjuvant immunotherapy for patients with surgically resectable EC. In this review, we discuss the rationale for neoadjuvant immunotherapy in patients with EC, summarize the current results of utilizing this strategy, review the planned and ongoing studies, and highlight the challenges and future research needs.
10.3389/fimmu.2022.1051841
Efficacy and safety of neoadjuvant immunotherapy in surgically resectable esophageal cancer: A systematic review and meta-analysis.
International journal of surgery (London, England)
BACKGROUND:Neoadjuvant immunotherapy for patients with locally advanced esophageal cancer (EC) has developed rapidly in recent years. The efficacy and safety outcomes may change the recommended neoadjuvant therapeutic regimens for patients with EC. METHODS:Systematic screening for articles focusing on the efficacy and safety of neoadjuvant immunotherapy in locally advanced and surgically resectable EC was performed using PubMed, Embase, Web of Science and international tumor congresses. Meta-analysis of non-comparative binary outcomes was carried out to combine the main results. The pooled results were compared with the traditional neoadjuvant chemotherapy (nCT) and chemoradiotherapy (nCRT) using direct comparative analysis. The results were expressed as the risk ratio (RR). RESULTS:A total of 20 articles with 621 patients were included in the present study. The pooled pathological complete response and major pathological response rates were 33.8% (95% CI: 29.6%-37.9%) and 53.5% (95% CI: 47.9%-59%), respectively, in the neoadjuvant immunotherapy combined with chemotherapy (nICT) group and 39.8% (95% CI: 27%-53.9%) and 88.8% (95% CI: 64.8%-97.2%) in the neoadjuvant immunotherapy combined with chemoradiotherapy (nICRT) group, respectively. In addition, the pooled grade 3-4 treatment-related adverse events (TRAEs) rate was 19.4% (95% CI: 11.5%-31.5%) in the nICT group. The results of direct comparison showed that compared with nCRT and nICRT, nICT could improve safety while achieving comparable efficacy. The results of subgroup analysis, sensitivity analysis and publication bias evaluation indicated that the above findings were stable and reliable. CONCLUSION:The current meta-analysis revealed that neoadjuvant immunotherapy in patients with locally advanced EC was safe and effective and nICT could be used as the recommended neoadjuvant therapeutic option for patients with EC. However, additional studies are urgently needed to reveal the long-term outcomes of neoadjuvant immunotherapy.
10.1016/j.ijsu.2022.106767
Evaluation of Clinical and Safety Outcomes of Neoadjuvant Immunotherapy Combined With Chemotherapy for Patients With Resectable Esophageal Cancer: A Systematic Review and Meta-analysis.
JAMA network open
Importance:A considerable number of clinical trials of neoadjuvant immunotherapy for patients with resectable esophageal cancer are emerging. However, systematic evaluations of these studies are lacking. Objective:To provide state-of-the-art evidence and normative theoretical support for neoadjuvant immunotherapy for locally advanced resectable esophageal cancer. Data Sources:PubMed, Embase, Cochrane Library, and ClinicalTrials.gov databases were searched for relevant original articles and conference proceedings that were published in English through April 1, 2022. Study Selection:Published phase 2 or 3 clinical trials that included patients with resectable stage I to IV esophageal cancer who received immune checkpoint inhibitors (ICIs) before surgery as monotherapy or in combination with other therapies. Data Extraction and Synthesis:The Preferred Reporting Items for Systematic Reviews and Meta-analyses and the Meta-analysis of Observational Studies in Epidemiology guidelines for meta-analysis were followed to extract data. A random-effects model was adopted if the heterogeneity was significant (I2 statistic >50%); otherwise, the common-effects model was used. Data analyses were conducted from April 2 to 8, 2022. Main Outcomes and Measures:Pathological complete response (pCR) rate and major pathological response (MPR) rate were considered to be the primary outcomes calculated for the clinical outcomes of neoadjuvant immunotherapy. Incidence of treatment-related severe adverse events was set as the major measure for the safety outcome. The rate of R0 surgical resection was summarized. Subgroup analyses were conducted according to histologic subtype and ICI types. Results:A total of 27 clinical trials with 815 patients were included. Pooled rates were 31.4% (95% CI, 27.6%-35.3%) for pCR and 48.9% (95% CI, 42.0-55.9%) for MCR in patients with esophageal cancer. In terms of safety, the pooled incidence of treatment-related severe adverse events was 26.9% (95% CI, 16.7%-38.3%). Most patients achieved R0 surgical resection (98.6%; 95% CI, 97.1%-99.6%). Regarding histologic subtypes, the pooled pCR rates were 32.4% (95% CI, 28.2%-36.8%) in esophageal squamous cell carcinoma and 25.2% (95% CI, 16.3%-35.1%) in esophageal adenocarcinoma. The pooled MPR rate was 49.4% (95% CI, 42.1%-56.7%) in esophageal squamous cell carcinoma. Conclusions and Relevance:This study found that neoadjuvant immunotherapy with chemotherapy had promising clinical and safety outcomes for patients with resectable esophageal cancer. Randomized clinical trials with long-term follow-up are warranted to validate the findings and benefits of ICIs.
10.1001/jamanetworkopen.2022.39778
Immunotherapy resistance in esophageal cancer: Possible mechanisms and clinical implications.
Frontiers in immunology
Esophageal cancer (EC) is a common malignant gastrointestinal (GI) cancer in adults. Although surgical technology combined with neoadjuvant chemoradiotherapy has advanced rapidly, patients with EC are often diagnosed at an advanced stage and the five-year survival rate remains unsatisfactory. The poor prognosis and high mortality in patients with EC indicate that effective and validated therapy is of great necessity. Recently, immunotherapy has been successfully used in the clinic as a novel therapy for treating solid tumors, bringing new hope to cancer patients. Several immunotherapies, such as immune checkpoint inhibitors (ICIs), chimeric antigen receptor T-cell therapy, and tumor vaccines, have achieved significant breakthroughs in EC treatment. However, the overall response rate (ORR) of immunotherapy in patients with EC is lower than 30%, and most patients initially treated with immunotherapy are likely to develop acquired resistance (AR) over time. Immunosuppression greatly weakens the durability and efficiency of immunotherapy. Because of the heterogeneity within the immune microenvironment and the highly disparate oncological characteristics in different EC individuals, the exact mechanism of immunotherapy resistance in EC remains elusive. In this review, we provide an overview of immunotherapy resistance in EC, mainly focusing on current immunotherapies and potential molecular mechanisms underlying immunosuppression and drug resistance in immunotherapy. Additionally, we discuss prospective biomarkers and novel methods for enhancing the effect of immunotherapy to provide a clear insight into EC immunotherapy.
10.3389/fimmu.2022.975986
A fibroblast-associated signature predicts prognosis and immunotherapy in esophageal squamous cell cancer.
Frontiers in immunology
Background:Current paradigms of anti-tumor therapies are not qualified to evacuate the malignancy ascribing to cancer stroma's functions in accelerating tumor relapse and therapeutic resistance. Cancer-associated fibroblasts (CAFs) has been identified significantly correlated with tumor progression and therapy resistance. Thus, we aimed to probe into the CAFs characteristics in esophageal squamous cancer (ESCC) and construct a risk signature based on CAFs to predict the prognosis of ESCC patients. Methods:The GEO database provided the single-cell RNA sequencing (scRNA-seq) data. The GEO and TCGA databases were used to obtain bulk RNA-seq data and microarray data of ESCC, respectively. CAF clusters were identified from the scRNA-seq data using the Seurat R package. CAF-related prognostic genes were subsequently identified using univariate Cox regression analysis. A risk signature based on CAF-related prognostic genes was constructed using Lasso regression. Then, a nomogram model based on clinicopathological characteristics and the risk signature was developed. Consensus clustering was conducted to explore the heterogeneity of ESCC. Finally, PCR was utilized to validate the functions that hub genes play on ESCC. Results:Six CAF clusters were identified in ESCC based on scRNA-seq data, three of which had prognostic associations. A total of 642 genes were found to be significantly correlated with CAF clusters from a pool of 17080 DEGs, and 9 genes were selected to generate a risk signature, which were mainly involved in 10 pathways such as NRF1, MYC, and TGF-Beta. The risk signature was significantly correlated with stromal and immune scores, as well as some immune cells. Multivariate analysis demonstrated that the risk signature was an independent prognostic factor for ESCC, and its potential in predicting immunotherapeutic outcomes was confirmed. A novel nomogram integrating the CAF-based risk signature and clinical stage was developed, which exhibited favorable predictability and reliability for ESCC prognosis prediction. The consensus clustering analysis further confirmed the heterogeneity of ESCC. Conclusion:The prognosis of ESCC can be effectively predicted by CAF-based risk signatures, and a comprehensive characterization of the CAF signature of ESCC may aid in interpreting the response of ESCC to immunotherapy and offer new strategies for cancer treatment.
10.3389/fimmu.2023.1199040