A carrier-free nanovaccine combined with cancer immunotherapy overcomes gemcitabine resistance.

Drug resistance is a significant challenge in cancer chemotherapy and is a primary factor contributing to poor recovery for cancer patients. Although drug-loaded nanoparticles have shown promise in overcoming chemotherapy resistance, they often carry a combination of drugs and require advanced design and manufacturing processes. Furthermore, they seldom approach chemotherapy-resistant tumors from an immunotherapy perspective. In this study, we developed a therapeutic nanovaccine composed solely of chemotherapy-induced resistant tumor antigens (CIRTAs) and the immune adjuvant Toll-like receptor (TLR) 7/8 agonist R848 (CIRTAs@R848). This nanovaccine does not require additional carriers and has a simple production process. It efficiently delivers antigens and immune stimulants to dendritic cells (DCs) simultaneously, promoting DCs maturation. CIRTAs@R848 demonstrated significant tumor suppression, particularly when used in combination with the immune checkpoint blockade (ICB) anti-PD-1 (αPD-1). The combined therapy increased the infiltration of T cells into the tumor while decreasing the proportion of regulatory T cells (Tregs) and modulating the tumor microenvironment, resulting in long-term immune memory. Overall, this study introduces an innovative strategy for treating chemotherapy-resistant tumors from a novel perspective, with potential applications in personalized immunotherapy and precision medicine.

Immunosuppressive tumor microenvironment in gastric signet-ring cell carcinoma.

Gastric signet-ring cell carcinoma (GSRCC) is a subtype of gastric cancer with distinct phenotype and high risk of peritoneal metastasis. Studies have shown that early GSRCC has a good prognosis, while advanced GSRCC is insensitive to radiotherapy, chemotherapy or immune checkpoint blockade therapy. With technological advancement of single-cell RNA sequencing analysis and cytometry by time of flight mass cytometry, more detailed atlas of tumor microenvironment (TME) in GSRCC and its association with prognosis could be investigated extensively. Recently, two single-cell RNA sequencing studies revealed that GSRCC harbored a unique TME, manifested as highly immunosuppressive, leading to high immune escape. The TME of advanced GSRCC was enriched for immunosuppressive factors, including the loss of CXCL13 +-cluster of differentiation 8+-Tex cells and declined clonal crosstalk among populations of T and B cells. In addition, GSRCC was mainly infiltrated by follicular B cells. The increased proportion of SRCC was accompanied by a decrease in mucosa-associated lymphoid tissue-derived B cells and a significant increase in follicular B cells, which may be one of the reasons for the poor prognosis of GSRCC. By understanding the relationship between immunosuppressive TME and poor prognosis in GSRCC and the underlying mechanism, more effective immunotherapy strategies and improved treatment outcomes of GSRCC can be anticipated.

Aristolochic acid-related renal cell carcinoma exhibits a distinct tumor-immune microenvironment favoring response to immune checkpoint blockade.

Immune checkpoint blockade (ICB) is currently the standard of care for metastatic renal cell carcinoma (RCC), but treatment responses remain unpredictable. Aristolochic acid (AA), a prevalent supplement additive in Taiwan, has been associated with RCC and induces signature mutations, although its effect on the tumor-immune microenvironment (TIME) is unclear. We aimed to investigate the immune profile of AA-positive RCCs and explore its potential role as a susceptible candidate for ICB. Tissue samples from 22 patients with clear cell RCC (ccRCC) were collected for whole-exome sequencing to determine the genetic features and AA mutational signature (the discovery cohort). The corresponding RNA was sent for NanoString PanCancer IO 360 gene expression analysis to explore the immunological features. The formalin-fixed, parafilm-embedded slides of ccRCCs were sent for multiplex immunohistochemistry/immunofluorescence stain using Vectra system to evaluate the TIME. Tissues from two patients with metastatic RCC demonstrating complete response to ICB were sent for studies to validate the findings (the index patients). The results showed that AA mutational signatures with high tumor mutational burden (TMB) were present in 31.81% of the tumors in the discovery cohort. Three distinct clusters were observed through NanoString analysis. Clusters 1 and 3 were composed mainly of AA-positive RCCs. Cluster 3 RCCs exhibited higher tumor inflammation signature scores and higher immune cell type scores. Vectra analysis revealed a higher percentage of CD15+ and BATF3+ cells in cluster 1, whereas the percentage of CD8+ cells was potentially higher in cluster 3. Strong AA mutational signatures were found in the tumors of two index patients, and both were grouped to cluster 3. In conclusion, AA may induce higher TMB and alter the immune microenvironment in RCCs, which makes the tumors more susceptible to ICB. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

CD8+ T cell exhaustion and its regulatory mechanisms in the tumor microenvironment: key to the success of immunotherapy.

A steady dysfunctional state caused by chronic antigen stimulation in the tumor microenvironment (TME) is known as CD8+ T cell exhaustion. Exhausted-like CD8+ T cells (CD8+ Tex) displayed decreased effector and proliferative capabilities, elevated co-inhibitory receptor generation, decreased cytotoxicity, and changes in metabolism and transcription. TME induces T cell exhaustion through long-term antigen stimulation, upregulation of immune checkpoints, recruitment of immunosuppressive cells, and secretion of immunosuppressive cytokines. CD8+ Tex may be both the reflection of cancer progression and the reason for poor cancer control. The successful outcome of the current cancer immunotherapies, which include immune checkpoint blockade and adoptive cell treatment, depends on CD8+ Tex. In this review, we are interested in the intercellular signaling network of immune cells interacting with CD8+ Tex. These findings provide a unique and detailed perspective, which is helpful in changing this completely unpopular state of hypofunction and intensifying the effect of immunotherapy.

Surgical and safety outcomes in patients with non-small cell lung cancer receiving neoadjuvant chemoimmunotherapy versus chemotherapy alone: A systematic review and meta-analysis.

Neoadjuvant immune checkpoint blockade (ICB) combined with chemotherapy has improved survival outcomes in locally-advanced non-small cell lung cancer (NSCLC). However, its impact on surgery has not been fully elucidated. We performed a systematic review and meta-analysis to compare surgical outcomes between neoadjuvant chemoimmunotherapy and chemotherapy alone in resectable NSCLC. PubMed and Embase were searched to select randomized controlled trials (RCTs) evaluating neoadjuvant ICB therapy for resectable NSCLC. The risk difference (RD) and odds ratio (OR) of outcomes such as surgical and R0 resection rates, overall complication rates, treatment-related adverse events (TRAEs), and AEs leading to cancellation of surgery were pooled using the random-effect model meta-analysis. We also evaluated the correlations between overall survival (OS) and surgical and safety outcomes. Eight RCTs with 3,387 patients were analyzed. Neoadjuvant chemoimmunotherapy was associated with improved surgical resection (RD 4.52 %, 95 % confidence interval [CI] 0.95 %-8.09 %, p = 0.01) and R0 resection (RD 4.04 %, 95 % CI 1.69 %-6.40 %, p = 0.0008) without increasing overall complications (RD -0.13 %, 95 % CI -5.14 %-4.88 %, p = 0.96), but an increase in surgery cancellation due to AEs (RD 1.15 %, 95 % CI 0.25 %- 2.05 %; p = 0.01) and grade 3-4 TRAEs (RD 3.42 %, 95 % CI 0.33 %-6.52 %, p = 0.03). OS did not show a direct significant correlation with surgical outcomes or TRAEs. Neoadjuvant chemoimmunotherapy improves resection rates but increases high-grade TRAEs and AEs leading to surgery cancellation. Nevertheless, incorporating ICB into neoadjuvant approach appears reasonable by improving surgical outcomes, potentially leading to improved survival in patients with locally-advanced NSCLC.

Nanotechnology for boosting ovarian cancer immunotherapy.

Ovarian cancer, often referred to as the "silent killer," is notoriously difficult to detect in its early stages, leading to a poor prognosis for many patients. Diagnosis is often delayed until the cancer has advanced, primarily due to its ambiguous and frequently occurring clinical symptoms. Ovarian cancer leads to more deaths than any other cancer of the female reproductive system. The main reasons for the high mortality rates include delayed diagnosis and resistance to treatment. As a result, there is an urgent need for improved diagnostic and treatment options for ovarian cancer. The standard treatments typically involve debulking surgery along with platinum-based chemotherapies. Among patients with advanced-stage cancer who initially respond to current therapies, 50-75% experience a recurrence. Recently, immunotherapy-based approaches to enhance the body's immune response to combat tumor growth have shown promise. Immune checkpoint inhibitors have shown promising results in treating other types of tumors. However, in ovarian cancer, only a few of these inhibitors have been effective because the tumor's environment suppresses the immune system and creates barriers for treatment. This hampers the effectiveness of existing immunotherapies. Nonetheless, advanced immunotherapy techniques and delivery systems based on nanotechnology hold promise for overcoming these challenges.

Biomarkers for evaluating the clinical response to immune checkpoint inhibitors in renal cell carcinoma (Review).

Renal cell carcinoma (RCC) is a highly aggressive neoplastic disease of the renal parenchyma that is characterized by an intrinsic resistance to cytotoxic chemotherapy; for this reason, curative treatment is only achieved through surgical intervention in its early stages. The successful treatment of advanced or metastatic RCC will require the combined use of novel targeted therapies such as tyrosine kinase inhibitors, vascular endothelial growth factor blockers and immune checkpoint blockade therapies. Unfortunately, not all patients are candidates for such treatments, and at present, it is not possible to predict a patient's therapeutic response or likelihood to develop treatment­associated complications. The present review described the literature focusing on the use of biomarkers for predicting patients' responses to therapies that induce immune checkpoint blockade in RCC.

Dynamics of tumor in situ fluid circulating tumor DNA in recurrent glioblastomas forecasts treatment efficacy of immune checkpoint blockade coupled with low-dose bevacizumab.

PURPOSE: Immune checkpoint blockade (ICB) therapies have shown efficacy in various tumors, but long-term responses in glioblastoma are less than 10%. Quantifying tumor in situ fluid circulating tumor DNA (TISF-ctDNA) and therapeutic dynamics may enable real-time GBM disease burden evaluation. This study explores the potential of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) dynamics in predicting treatment efficacy. METHODS: TISF and peripheral blood samples were collected from patients with recurrent glioblastoma (rGBM) undergoing tislelizumab (a programmed death 1 inhibitor) combined with low-dose bevacizumab (an anti-vascular endothelial growth factor antibody) treatment before and during each immunotherapy cycle. Biomarkers evaluated included TISF-ctDNA, measured using Next Generation Sequencing (NGS), and host inflammation markers such as the platelet-to-lymphocyte ratio (PLR). RESULTS: All 32 patients received tislelizumab plus low-dose bevacizumab regularly. The median progression-free survival (PFS) was 4.0 months, and overall survival (OS) was 22.3 months. An analysis of 19 patients with continuous evaluable TISF showed baseline TISF-ctDNA abundance did not correlate with OS (p = 0.23) or PFS (p = 0.23). However, a change in TISF-ctDNA maximal Somatic Variant Allelic Frequency (MVAF) after six treatment cycles predicted both PFS (p = 0.02) and OS (p < 0.0001). Lower baseline PLR also correlated with better survival outcomes. CONCLUSION: The combination of tislelizumab and low-dose bevacizumab therapy appears to be effective in extending both OS and PFS in rGBM patients. Continuous TISF-ctDNA testing shows potential utility in complementing radiological monitoring. The temporal change pattern of TISF MVAF is more predictive of immunotherapy response than imaging. PLR before immunotherapy can screen patients likely to benefit from tislelizumab plus low-dose bevacizumab therapy. TRIAL REGISTRATION: The trial registration number: NCT05502991; Date of registration: 2022-08-14.

The role of microbial indole metabolites in tumor.

The gut microbiota can produce a variety of microbial-derived metabolites to influence tumor development. Tryptophan, an essential amino acid in the human body, can be converted by microorganisms via the indole pathway to indole metabolites such as Indole-3-Lactic Acid (ILA), Indole-3-Propionic Acid (IPA), Indole Acetic Acid (IAA) and Indole-3-Aldehyde (IAld). Recent studies have shown that indole metabolites play key roles in tumor progression, and they can be used as adjuvant regimens for tumor immunotherapy or chemotherapy. Here, we summarize recent findings on the common microbial indole metabolites and provide a review of the mechanisms of different indole metabolites in the tumor microenvironment. We further discuss the limitations of current indole metabolite research and future possibilities. It is expected that microbial indole metabolites will provide new strategies for clinical therapy.

Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma.

Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment.

Size matters: integrating tumour volume and immune activation signatures predicts immunotherapy response.

Immune checkpoint inhibitors (ICIs) have transformed cancer treatment, providing significant benefit to patients across various tumour types, including melanoma. However, around 40% of melanoma patients do not benefit from ICI treatment, and accurately predicting ICI response remains challenging. We now describe a novel and simple approach that integrates immune-associated transcriptome signatures and tumour volume burden to better predict ICI response in melanoma patients. RNA sequencing was performed on pre-treatment (PRE) tumour specimens derived from 32 patients with advanced melanoma treated with combination PD1 and CTLA4 inhibitors. Of these 32 patients, 11 also had early during treatment (EDT, 5-15 days after treatment start) tumour samples. Tumour volume was assessed at PRE for all 32 patients, and at first computed tomography (CT) imaging for the 11 patients with EDT samples. Analysis of the Hallmark IFNγ gene set revealed no association with ICI response at PRE (AUC ROC curve = 0.6404, p = 0.24, 63% sensitivity, 71% specificity). When IFNg activity was evaluated with tumour volume (ratio of gene set expression to tumour volume) using logistic regression to predict ICI response, we observed high discriminative power in separating ICI responders from non-responders (AUC = 0.7760, p = 0.02, 88% sensitivity, 67% specificity); this approach was reproduced with other immune-associated transcriptomic gene sets. These findings were further replicated in an independent cohort of 23 melanoma patients treated with PD1 inhibitor. Hence, integrating tumour volume with immune-associated transcriptomic signatures improves the prediction of ICI response, and suggest that higher levels of immune activation relative to tumour burden are required for durable ICI response.

A Mechanical Immune Checkpoint Inhibitor Stiffens Tumor Cells to Potentiate Antitumor Immunity.

Tumor progression is associated with tumor-cell softening. Improving the stiffness of the tumor cells can make them more vulnerable to lymphocyte-mediated attack. Tumor cell membranes typically exhibit higher cholesterol levels than normal cells, making tumor cells soft. Herein, we demonstrate a mechanical immune checkpoint inhibitor (MICI) formulated by cyclodextrin (CD) lipids and fusogenic lipids. Through fusing CD lipids into the tumor cell membrane using a fusogenic liposome formulation, the cholesterol in the plasma membrane is reduced due to the specific host-guest interactions between CD lipid and cholesterol. As a result, tumor cells are stiffened, and the activation of lymphocytes (including NK and cytotoxic effector T cells) is improved when contacting the stiffened tumor cells, characterized by robust degranulation and effector cytokine production. Notably, this treatment has negligible influence on the infiltration and proliferation of lymphocytes in tumor tissues, confirming that the enhanced antitumor efficacy should result from activating a specific number of lymphocytes caused by direct regulation of the tumor cell stiffness. The combination of MICIs and clinical immunotherapies enhances the lymphocyte-mediated antitumor effects in two tumor mouse models, including breast cancer and melanoma. Our research also reveals an unappreciated mechanical dimension to lymphocyte activation.

Type I Diabetes Mellitus impairs cytotoxic immunity through CEACAM5 upregulation in colorectal cancer : Exploring the intersection of autoimmune dysfunction and cancer progression: the role of NF-κB p65 in colorectal cancer.

Type 1 diabetes (T1D) is characterized by an autoimmune-mediated destruction of pancreatic beta cells and a chronic inflammatory state, which may influence the progression of colorectal cancer (CRC) through immune system dysregulation and enhanced tumor immune evasion. This study aims to elucidate the role of p65 in modulating the tumor microenvironment in CRC within the context of T1D and to determine how this modulation affects tumor growth, immune cell infiltration, and the expression of immune evasion molecules such as CEACAM5. NOD mice, which model T1D, were inoculated with MC38 colon carcinoma cells engineered to knock down p65. Tumor growth was monitored, and the tumor microenvironment was analyzed using flow cytometry to assess the infiltration of immune cells. The expression of Ki-67 and CEACAM5 in tumor cells was also evaluated. Additionally, in vitro assays were conducted to study the proliferation and activation of T cells co-cultured with tumor cells. Knockdown of p65 in tumor cells significantly inhibited tumor growth in NOD mice. This was accompanied by an increased infiltration of cytotoxic CD8+ T cells and no significant change in CD4+ or Foxp3 + T regulatory cells within the tumor microenvironment. There was a notable reduction in the expression of Ki-67 and CEACAM5, indicating decreased proliferation and potential immune evasion capabilities of the tumor cells. Our findings demonstrate that the NF-κB p65 subunit plays a crucial role in promoting tumor growth and modulating the immune microenvironment in CRC, particularly in the context of T1D. Knocking down p65 not only reduces tumor progression but also enhances the anti-tumor immune response by decreasing immune evasion mechanisms. These results suggest that targeting the NF-κB pathway may be a viable strategy to improve the efficacy of cancer immunotherapy, especially in patients with autoimmune diseases like T1D. Physical activity enhances the effect of immune checkpoint blockade by inhibiting the intratumoral HIF1-α/CEACAM5 axis.

SET facilitates immune escape of microsatellite stability colorectal cancer by inhibiting c-Myc degradation.

Microsatellite stability (MSS) colorectal cancer (CRC) exhibits a low mutation load and poor immunogenicity, contributing to immune escape of tumor cells and less benefit from immune checkpoint blockade (ICB) treatment. The mechanisms underlying immunotherapeutic resistance in MSS CRC remain to be elucidated. Here, we identified that nuclear proto-oncogene SET is significantly higher expressed in MSS CRC compared to microsatellite instability (MSI) CRC and facilitates immune escape of MSS CRC. Mechanistically, SET represses the expression of C-C motif chemokine ligand 5 (CCL5) and upregulates mismatch repair (MMR) proteins expression in a c-Myc-dependent manner, which inhibits infiltration and migration of CD8+ T cells to tumor tissues and results in low immunogenicity in MSS CRC. In addition, we found that SET impairs ubiquitination and proteasomal degradation of c-Myc by disrupting the interaction between E3 ligase FBXW7 and c-Myc. Moreover, SET inhibition enhances the response to immunotherapy in MSS CRC in vivo. Overall, this study reveals the critical roles and posttranslational regulatory mechanism of SET in immune escape and highlights the SET/c-Myc axis as a potential target for immunotherapy of MSS CRC that have implications for targeting a unique aspect of this disease.

The baseline hemoglobin level is a positive biomarker for immunotherapy response and can improve the predictability of tumor mutation burden for immunotherapy response in cancer.

Purpose: Because only a subset of cancer patients can benefit from immunotherapy, identifying predictive biomarkers of ICI therapy response is of utmost importance. Methods: We analyzed the association between hemoglobin (HGB) levels and clinical outcomes in 1,479 ICIs-treated patients across 16 cancer types. We explored the dose-dependent associations between HGB levels and survival and immunotherapy response using the spline-based cox regression analysis. Furthermore, we investigated the associations across subgroups of patients with different clinicopathological characteristics, treatment programs and cancer types using the bootstrap resampling method. Results: HGB levels correlated positively with clinical outcomes in cancer patients receiving immunotherapy but not in those without immunotherapy. Moreover, this association was independent of other clinicopathological characteristics (such as sex, age, tumor stage and tumor mutation burden (TMB)), treatment program and cancer type. Also, this association was independent of the established biomarkers of immunotherapy response, including TMB, PD-L1 expression and microsatellite instability. The combination of TMB and HGB level are more powerful in predicting immunotherapy response than TMB alone. Multi-omics analysis showed that HGB levels correlated positively with antitumor immune signatures and negatively with tumor properties directing antitumor immunosuppression, such as homologous recombination defect, stemness and intratumor heterogeneity. Conclusion: The HGB measure has the potential clinical value as a novel biomarker of immunotherapy response that is easily accessible from clinically routine examination. The combination of TMB and HGB measures have better predictive performance for immunotherapy response than TMB.

Novel tumor gene expression signatures improve the overall survival prediction efficiency over tumor mutation burden and PD-L1 expression in bladder carcinoma with checkpoint blockade immunotherapy.

Although immune checkpoint blockade therapy (ICBT) has revolutionized cancer treatment with good therapeutic response in a number of human cancers, including bladder cancer, many cancers still do not respond to ICBT. Analyzing genetic signatures helps the understanding of underlying biological mechanisms. Here, based on two cohorts of bladder cancer patients receiving ICBT, we identified three novel ICBT-associated signatures in the bladder cancer microenvironment, involving genomic stability, angiogenesis and RNA regulatory, which affect PD-L1 expression and patient response to ICBT. The combinations of these signatures with TMB or PD-L1 expression improved the overall survival prediction efficiency over TMB and PD-L1 expression alone for patients receiving ICBT. Moreover, we utilized two methods to search potential drugs or small-molecules that have an impact on ICBT-associated signatures. This study provides new molecular insight into ICBT response of bladder cancer and has the potential to improve the prediction accuracy for patients to benefit from ICBT.

Small-Molecule Therapeutics Achieve Multiple Mechanism-Mediated Sensitizations of Colorectal Cancer to Immune Checkpoint Blockade via Neutrophil Micropharmacies.

Immune checkpoint blockade (ICB) therapy has been approved for colorectal cancer (CRC). However, response rates are variable and often <50%. The low tumor immunogenicity and immunosuppressive tumor microenvironment (TME) jointly contribute to this suboptimal response rate. This study confirmed the potential of combining immunogenic cell death (ICD) inducer irinotecan (IRI) and transforming growth factor-ß (TGF-ß) inhibitor galunisertib (GAL) to improve tumor immunogenicity and remodel the immunosuppressive TME. Moreover, to ameliorate the in vivo delivery barriers associated with small molecules, neutrophil micropharmacies (NOG) were developed for the codelivery of IRI and GAL, which loaded the commercial liposome formulation of IRI (ONIVYDE, ONI) intracellularly and conjugated the pH-responsive GAL liposome (GLP) on the cell surface. This neutrophil-based formulation resulted in a >4-fold increase in the ratios of the amount of both IRI and GAL accumulated in tumors to the dosage administration, effectively achieving multiple mechanism-mediated sensitization of CRC to ICB therapy.

Polyphenol-Based Self-Assembled Nanomedicine for a Three-Pronged Approach to Reversing Tumor Immunosuppression.

The challenges of multi-pathway immune resistance and systemic toxicity caused by the direct injection of immune checkpoint inhibitors are critical factors that compromise the effectiveness of clinical immune checkpoint blockade therapy. In this context, natural polyphenols have been employed as the primary component to construct a targeted and acid-responsive PD-L1 antibody (αPD-L1) delivery nanoplatform. This platform incorporates garcinol, an inhibitor of the Nuclear Factor Kappa-B (NF-κB) signaling pathway, to regulate pro-tumor immune escape cytokines and regulatory T cells. Additionally, the nanoplatform has been verified to induce immunogenic cell death (ICD), which promotes the maturation of dendritic cells and enhances the activity of cytotoxic T lymphocytes. In vivo and in vitro experimental results demonstrated that the nanoplatform can boost the immune response through a PD-L1 and NF-κB blocking/ICD inducing three-pronged strategy, thereby effectively combating tumor growth and metastasis.

E-cigarette exposure disrupts antitumor immunity and promotes metastasis.

Electronic cigarettes (e-cigarettes) are thought to pose low risk of cancer because the components of e-cigarette liquid are not carcinogens. We analyzed the effects of the two major components, PG/VG and nicotine, on tumor development in preclinical models. We found that PG/VG promoted tumor cell migration in migration assays and contributed to more aggressive, metastatic, and immunosuppressive tumors in vivo, aggravated by the presence of nicotine. Whole body exposure of mice to PG/VG and nicotine rendered animals more susceptible to developing tumors with high frequencies of infiltrating proinflammatory macrophages expressing IL-6 and TNFα. Moreover, tumor-infiltrating and circulating T cells in e-cigarette exposed mice showed increased levels of immune checkpoints including CTLA4 and PD-1. Treatment with anti-CTLA4 antibody was able to abrogate metastasis with no detrimental effects on its ability to induce tumor regression in exposed mice. These findings suggest that the major components used in e-cigarette fluid can impact tumor development through induced immunosuppression.