Release Of Tumor Antigens Research Articles

Photoacoustic mediated multifunctional tumor antigen trapping nanoparticles inhibit the recurrence and metastasis of ovarian cancer by enhancing tumor immunogenicity

The hypoimmunogenicity of tumors is one of the main bottlenecks of cancer immunotherapy. Enhancing tumor immunogenicity can improve the efficacy of tumor immunotherapy by increasing antigen exposure and presentation, and establishing an inflammatory microenvironment. Here, a multifunctional antigen trapping nanoparticle with indocyanine green (ICG), aluminum hydroxide (Al(OH)3) and oxaliplatin (OXA) (PPIAO) has been developed for tumor photoacoustic/ultrasound dual-modality imaging and therapy. The combination of photothermal/photodynamic therapy and chemotherapy induced tumor antigen exposure and release through immunogenic death of tumor cells. A timely capture and storage of antigens by aluminum hydroxide enabled dendritic cells to recognize and present those antigens spatiotemporally. In an ovarian tumor model, the photoacoustic-mediated PPIAO NPs combination therapy achieved a transition from “cold tumor” to “hot tumor” that promoted more CD8+ T lymphocytes activation in vivo and intratumoral infiltration, and successfully inhibited the growth of primary and metastatic tumors. An in situ tumor vaccine effect was produced from the treated tumor tissue, assisting mice against the recurrence of tumor cells. This study provided a simple and effective personalized tumor vaccine strategy for better treatment of metastatic and recurrent tumors. The developed multifunctional tumor antigen trapping nanoparticles may be a promising nanoplatform for integrating multimodal imaging monitoring, tumor treatment, and tumor vaccine immunotherapy.

Tumor Microenvironment-Activated Hydrogel Platform with Programmed Release Property Evokes a Cascade-Amplified Immune Response against Tumor Growth, Metastasis and Recurrence.

In situ tumor vaccines (ITV) have been recognized as a promising antitumor strategy since they contain the entire tumor-specific antigens, avoiding tumor cells from evading immune surveillance due to antigen loss. However, the therapeutic benefits of ITV are limited by obstacles such as insufficient antigen loading, inadequate immune system activation, and immunosuppressive tumor microenvironments (TME). Herein, a tumor microenvironment-activated hydrogel platform (TED-Gel) with programmed drug release property is constructed for cascaded amplification of the anti-tumor immune response elicited by ITV. Both doxorubicin (Dox) and cytosine-phosphate-guanosine oligodeoxynucleotides (CpG) are released first, in which Dox induces immunogenic tumor cell death causing additional tumor antigen release and leading the dying primary tumor cells into autologous tumor vaccine, and the released CpG promotes antigen presenting cell activation. Subsequently, the decomposed scaffold materials in conjunction with CpG, turn the anti-inflammatory M2-like macrophages into the M1 type, reversing the immunosuppressive TME. With decomposition of the TED-Gel, large amounts of macromolecule anti-PD-L1 antibodies are liberated, reinvigorating the exhausted effector T cells. In vivo studies demonstrate that TED-Gel significantly inhibits the primary, distant and rechallenged tumor growth. Overall, the simple and powerful TED-Gel provides an alternative strategy for the future development of tumor vaccines with broad application.

Radiotherapy Enhance the Immune Checkpoint Inhibitors Efficacy in Advanced Liver Cancer

<h3>Purpose/Objective(s)</h3> Many patients with advanced liver cancer receiving immunotherapy show primary or acquired resistance. Radiotherapy (RT) is an integral component in the treatment of solid cancers, including HCC. Radiation mediates localized tumor killing and further leads to increased tumor antigen release, improving antigen presentation and T-cell infiltration, thereby potentiating the action of immune checkpoint inhibitors (ICIs). Here we aim to investigate the efficacy and safety of radiation therapy (RT) plus ICIs in advanced liver cancer. <h3>Materials/Methods</h3> Of the 180 patients enrolled from August 2018 to June 2021, 87 patients were treated with the combination of RT and ICIs (RT-ICIs cohort); 93 patients were given ICIs therapy (ICIs cohort). Radiotherapy was conducted within 60 days or concurrently of starting programmed death receptor or ligand-1 (PD-1 or PD-L1) inhibitor therapy. Propensity-score matched estimates were used to reduce bias when evaluating the clinical outcomes. <h3>Results</h3> In the matched cohorts (49 pairs), the median progression-free survival (PFS) and overall survival (OS) in the RT-ICIs cohort were significantly longer than those in the ICIs cohort (PFS, 8.1 vs. 3.0 months, <i>p</i> < 0.001; OS, 21.7 vs. 13.3 months, <i>p</i> = 0.023). The RT-ICIs cohort also achieved higher objective response rate (ORR) and disease control rate (DCR) than those in the ICIs cohort (ORR 49.0% vs. 22.4%, <i>p</i> = 0.006; DCR 71.4% vs. 32.7%, <i>p</i> < 0.001). At multivariate analysis, RT-ICIs treatment was an independent factor for PFS (hazard ratio [HR] 0.45; 95% CI 0.294-0.668; <i>p</i> < 0.001) and OS (HR 0.530; 95% CI 0.287-0.976; <i>p</i> = 0.042). No significant differences in toxic effects between cohorts were observed in the analysis. <h3>Conclusion</h3> Radiotherapy enhances the ICIs efficacy in patients with advanced liver cancer by improving control of the systemic disease without an increase in toxic effects. Since this is a small retrospective study, a prospective randomized trial is ongoing to validate this finding (ClinicalTrials.gov identifier: NCT03857815).

Nanobubbles containing PD-L1 Ab and miR-424 mediated PD-L1 blockade, and its expression inhibition to enable and potentiate hepatocellular carcinoma immunotherapy in mice

Immune checkpoint inhibitors (ICI) therapy is the main type of immunotherapy for cancer. Current clinical trials are focused on enhancing anti-tumor effects through combinations of multiple ICIs with agents that cause tumor cell death and release tumor antigens. In this study, weprepared nanobubbles (NBs) to load programmed death-ligand 1 (PD-L1) antibody andmiR-424gene to evaluate the combined anti-tumor activity of the targeted NBs.The miR-424 gene was chosen to be an anti-tumor gene, which can target PD-L1 and Bcl-2, through bioinformatics analysis and target gene verification. Then, PD-L1 Ab/miR-424-NBs were prepared by thin-film hydration. The optimal shape, size, and character of the NBs were determined by scanning electron microscopy and Zeta potential study. In addition, the antibody binding rate and gene loading of the targeted NBs were studied by agarose gel electrophoresis and flow cytometry, respectively. The synergistic immunotherapeutic effect of anti-PD-L1 antibody andmiR-424in vivo and their mechanism were evaluated using an H22 hepatoma transplanted tumor model in mice,whichproved that the targeted NBs mediated the PD-L1 antibody toblock the PD-1/PD-L1 signaling pathway and the transfected miR-424gene to downregulate the PD-L1 expression of tumor cells, both of which enhanced the antitumor immune effect mediated by T cells. It was also found that the targeted NBs activated T cells, which released a large number of cytokines, such as IFN-γ and IL-2, to recruit and activate macrophages and NK cells. It is suggested that ultrasound-mediated PD-L1 antibody NBs delivering miR-424 can inhibit the growth of subcutaneously transplanted hepatocellular carcinoma in terms of apoptosis and immunity. Therefore, ultrasound-mediated targeted NBs are a potential effective carrier for liver cancer, and PD-L1 antibody and miR-424 have a synergistic anti-tumor immunotherapy effect.

Flagging the Merited Lesions-Fibroblast 1 and 4 Imaging to Map the Key Avid Domains for Spiked Antigenicity Using SBRT In Situ Vaccination and Metronomic Radiation with Anti PDL-1 Therapy for Augmented Abscopal-Radscopal Responses in Disseminated Cancers

<h3>Purpose/Objective(s)</h3> Immune stimulating effects of SBRT (stereotactic body radiotherapy) for releasing tumor antigens and the immuno-modulatory property of low dose radiation has been under evaluation over years. Conceptual Radscopal effect for lesions receiving a non-tumoricidal scattered low dose radiation showing abscopal responses led to the concept of combining SBRT to highly avid larger metastatic lesions and low dose radiation to smaller lesions is exciting. However, choosing the right lesions for SBRT to release adequate and appropriate tumor antigen spike to cause a systemic response has been a challenge and area of interest. Cancer Associated Fibroblasts (CAF) 1 and 4 can produce growth factors and cytokines such as transforming growth factor-β (TGF-β) and vascular endothelial growth factor (VEGF) to promote angiogenesis and recruit immunosuppressive cells into the tumor stroma leading to immune evasion and resistant immune microenvironment. Fibroblast Activated protein tagged to CAF 1 and 4 whole body Molecular imaging aids us in identifying regions. Based on the avidity values of CAF 1 and 4 tagged imaging, the most immune resistant (CAF Rich) target lesions were chosen for SBRT in our study. Prominent usage of Anti PDL-1 inhibitors has been proven to be beneficial in disseminated cancers, concept of SBRT with metronomic radiation could be used as immune potentiator with accurate mapping of Immune resistant areas. <h3>Materials/Methods</h3> Five patients with disseminated cancers with indications for approved immune check point inhibitors were recruited after institutional ethical committee clearance. Patients received at least 3 cycles of check point inhibitor therapy prior to initiation of immuno-rad therapy. Based on CAF molecular imaging, 1-3 lesions with maximal avidity >10 standard uptake value were chosen for SBRT to a dose of 24 Gy in 3 fractions while all other metastatic less avid smaller lesions received Low dose 1 Gy metronomic radiotherapy using Image guided radiotherapy. Patients were continued on immunotherapy for 3 more cycles before a re-assessment molecular imaging was done. <h3>Results</h3> Nasopharyngeal (NPC), hepatocellular (HCC), 2 lung and renal cell cancer (RCC) patients were recruited. No grade 2 or above normal tissue toxicity was noted. <h3>Conclusion</h3> Effectively tackling the tumor immune evasion mechanisms by choosing the right lesions for SBRT acting as an in situ-vaccination by extensive release of antigens based on individual CAF biomarker profiling would ultimately aid in improving responses to Immunotherapy. The early results of our study are encouraging.

Combining of Oncolytic Virotherapy and Other Immunotherapeutic Approaches in Cancer: A Powerful Functionalization Tactic.

Oncolytic viruses have found a good place in the treatment of cancer. Administering oncolytic viruses directly or by applying genetic changes can be effective in cancer treatment through the lysis of tumor cells and, in some cases, by inducing immune system responses. Moreover, oncolytic viruses induce antitumor immune responses via releasing tumor antigens in the tumor microenvironment (TME) and affect tumor cell growth and metabolism. Despite the success of virotherapy in cancer therapies, there are several challenges and limitations, such as immunosuppressive TME, lack of effective penetration into tumor tissue, low efficiency in hypoxia, antiviral immune responses, and off-targeting. Evidence suggests that oncolytic viruses combined with cancer immunotherapy-based methods such as immune checkpoint inhibitors and adoptive cell therapies can effectively overcome these challenges. This review summarizes the latest data on the use of oncolytic viruses for the treatment of cancer and the challenges of this method. Additionally, the effectiveness of mono, dual, and triple therapies using oncolytic viruses and other anticancer agents has been discussed based on the latest findings.

Extracellular-Vesicle-Based Drug Delivery Systems for Enhanced Antitumor Therapies through Modulating the Cancer-Immunity Cycle.

Although immunotherapy harnessing activity of the immune system against tumors has made great progress, the treatment efficacy remains limited in most cancers. Current anticancer immunotherapy is primarily based on T-cell-mediated cellular immunity, which highly relies on efficiency of triggering the cancer-immunity cycle, namely, tumor antigen release, antigen presentation by antigen presenting cells, T cell activation, recruitment and infiltration of T cells into tumors, and recognition and killing of tumor cells by T cells. Unfortunately, these immunotherapies are restricted by inefficient drug delivery and acting on only a single step of the cancer-immunity cycle. Due to high biocompatibility, low immunogenicity, intrinsic cell targeting, and easy chemical and genetic manipulation, extracellular vesicle (EV)-based drug delivery systems are widely used to amplify anticancer immune responses by serving as an integrated platform for multiple drugs or therapeutic strategies to synergistically activate several steps of cancer-immunity cycle. This review summarizes various mechanisms related to affecting cancer-immunity cycle disorders. Meanwhile, preparation and application of EV-based drug delivery systems in modulating cancer-immunity cycle are introduced, especially in the improvement of T cell recruitment and infiltration into tumors. Finally, opportunities and challenges of EV-based drug delivery systems in translational clinical applications are briefly discussed.

Quercetin-ferrum nanoparticles enhance photothermal therapy by modulating the tumor immunosuppressive microenvironment

Photothermal therapy (PTT) was reported to induce synergistic immunogenic cell death (ICD) which may convert tumor cells into “therapeutic vaccines”. However, this is often insufficient to prevent tumor recurrence, in part because of the immunosuppressive microenvironment in tumors. Therefore, remodeling tumor microenvironment is of great importance to enhance the therapeutic efficacy of PTT. We herein fabricated a versatile nano-photosensitizer by assembling quercetin and Ferrum ion (QFN). The released quercetin from QFN could reduce programmed death ligand 1 (PD-L1) in tumor cells by inhibiting the phosphorylation of JAK2 and STAT3, and reshape extracellular matrix (ECM) by down-regulating α-SMA+ fibroblast in tumors. Moreover, QFN could capture tumor antigen and deliver it to the tumor-draining lymph nodes after PTT, which further enhanced the activation of antigen-presenting cells. As a result, QFN-based PTT eliminated melanoma and induced long-term immune memory to prevent tumor metastasis and recurrence. This study provides an effective and translationally feasible photothermic agent for photothermal/immunotherapy. Statement of significanceThe efficacy of photothermal therapy (PTT) in cancer treatment is often limited by the immunosuppressive microenvironment in tumors. Herein, we prepared a versatile photosensitizer by assembling quercetin and Ferrum ion (QFN). Upon near-infrared light irradiation, QFN-PTT induced cancer cells destruction and tumor antigen release. QFN then captured antigen and delivered it to the tumor-draining lymph nodes, thus promoting dendritic cell maturation and T cells activation. Quercetin released from QFN in tumors improved T cells infiltration and activation in tumor by regulating immunosuppressive microenvironment. The QFN-PTT-treated mice exhibited significantly elongated survival time, and gained strong anti-tumor immune memory to prevent tumor metastasis and recurrence. Thus, this work provided a simple and versatile photothermic agent, and it has important implications for designing effective and translationally feasible photosensitizers for PTT.

Sequentially sustained release of anticarcinogens for postsurgical chemoimmunotherapy.

Postsurgical treatment is of great importance to combat tumor recurrence and metastasis. Anti-CD47 antibodies (aCD47) can block the CD47-signal regulatory protein-alpha (CD47-SIRPα) pathway to restore immunity. Here, an in-situ gel implantation was engineered by crosslinking chitosan (CS) and pullulan (Pul) for postsurgical treatment. A highly selected chemotherapeutic, cyclopamine (Cyc), encapsulated in liposomes (Cyc-Lip) was co-loaded with aCD47 in gels for chemoimmunotherapy. Importantly, a sequential drug release kinetics can be achieved. Nanotherapeutics were confirmed to be released prior to aCD47 in a burst-release manner, which was benefit for immediately killing residual tumor cells followed by releasing tumor antigens. Meanwhile, aCD47 was released in a sustained-release manner to restore macrophage functions and exert anti-tumor immune responses. Afterwards, the efficacy of in-situ chemoimmunotherapy was confirmed on 4T1 mouse breast cancer models, which could not only efficiently augment anti-tumor effect to inhibit tumor recurrence but also establish a long-term immune memory to combat tumor metastasis.

Localized ablative immunotherapy drives de novo CD8+ T-cell responses to poorly immunogenic tumors

BackgroundLocalized ablative immunotherapies hold great promise in stimulating antitumor immunity to treat metastatic and poorly immunogenic tumors. Tumor ablation is well known to release tumor antigens and danger-associated molecular patterns...

Oral Nanomotor-Enabled Mucus Traverse and Tumor Penetration for Targeted Chemo-Sono-Immunotherapy against Colon Cancer.

The therapeutic outcomes of oral nanomedicines against colon cancer are heavily compromised by their lack of specific penetration into the internal tumor, favorable anti-tumor activity, and activation of anti-tumor immunity. Herein, hydrogen peroxide (H2 O2 )/ultrasound (US)-driven mesoporous manganese oxide (MnOx )-based nanomotors are constructed by loading mitochondrial sonosensitizers into their mesoporous channels and orderly dual-functionalizing their surface with silk fibroin and chondroitin sulfate. The locomotory activities and tumor-targeting capacities of the resultant nanomotors (CS-ID@NMs) are greatly improved in the presence of H2 O2 and US irradiation, inducing efficient mucus-traversing and deep tumor penetration. The excess H2 O2 in the tumor microenvironment (TME) is decomposed into hydroxyl radicals and oxygen by an Mn2+ -mediated Fenton-like reaction, and the produced oxygen participates in sonodynamic therapy (SDT), yielding abundant singlet oxygen. The combined Mn2+ -mediated chemodynamic therapy and SDT cause effective ferropotosis of tumor cells and accelerate the release of tumor antigens. Importantly, animal experiments reveal that the treatment of combining oral hydrogel (chitosan/alginate)-embedding CS-ID@NMs and immune checkpoint inhibitors can simultaneously suppress the growth of primary and distal tumors through direct killing, reversion of immunosuppressive TME, and potentiation of systemic anti-tumor immunity, demonstrating that the CS-ID@NM-based platform is a robust oral system for synergistic treatment of colon cancer.

The marine natural product mimic MPM-1 is cytolytic and induces DAMP release from human cancer cell lines

Bioprospecting contributes to the discovery of new molecules with anticancer properties. Compounds with cytolytic activity and the ability to induce immunogenic cell death can be administered as intratumoral injections with the aim to activate anti-tumor immune responses by causing the release of tumor antigens as well as damage-associated molecular patterns (DAMPs) from dying cancer cells. In the present study, we report the cytolytic and DAMP-releasing effects of a new natural product mimic termed MPM-1 that was inspired by the marine Eusynstyelamides. We found that MPM-1 rapidly killed cancer cells in vitro by inducing a necrosis-like death, which was accompanied by lysosomal swelling and perturbation of autophagy in HSC-3 (human oral squamous cell carcinoma) cells. MPM-1 also induced release of the DAMPs adenosine triphosphate (ATP) and high mobility group box 1 (HMGB1) from Ramos (B-cell lymphoma) and HSC-3 cells, as well as cell surface expression of calreticulin in HSC-3 cells. This indicates that MPM-1 has the ability to induce immunogenic cell death, further suggesting that it may have potential as a novel anticancer compound.

1700P Radiation therapy elicits a consistent myeloid and lymphoid immune response in breast and rectal cancer

Radiotherapy (RT) is broadly used for cancer treatment, including early breast (eBRCA) and rectal cancers (RC). However, many components of the tumor microenvironment (TME) contribute to RT resistance. RT induces cancer cell death resulting in tumor antigen release that triggers the recruitment of a variety of immune cells that can act either stimulatory or suppressive on anti-tumor immunity. A deeper understanding of the immune suppressive components of anti-tumor immunity is integral to discover novel treatments to improve RT effectiveness. In this study, RT induced transcriptional changes were identified that associate with cellular consequences that may promote radio-resistance. Moreover, the delineation of tumor-specific changes can help selecting patients undergoing RT that are likely to have tumor recurrence. Datasets of patients with eBRCA (Horton 2015) and RC (Petty 2009) that received single-dose RT were analyzed. Gene signatures of immune activation and suppression were summarized for each patient as an average of the standard score and evaluated at the baseline and after RT. Fractions of immune cell populations were estimated by cell type deconvolution using xCell (Aran 2017) and compared pre and post RT. Evaluation of gene signatures of immune activation (inflammatory response, T-cell inflammation) and immune suppression (M2 macrophages, TGF-b signaling) in eBRCA and RC patients showed a consistent increase in pre compared to post RT. The comparison of score fold-change (pre-post RT) showed a stronger increase of the signatures in RC compared to eBRCA, with similar change for the TGF-b signaling score. Cell type deconvolution analysis showed that M1 and M2 macrophages and cancer-associated fibroblasts increase after RT in both tumor types, while NK T cells decrease. The main differences were found in neutrophils and regulatory T cells that have opposite trends in the two tumor types. The results showed an overall increase of immune activation and suppression genes after RT, more pronounced in RC compared to eBRCA patients. Moreover, the TME of RC showed a more immune-suppressive profile with an increase of regulatory T cells in addition to M2 macrophages.

Intratumoral administration of CD1c (BDCA-1)+ and CD141 (BDCA-3)+ myeloid dendritic cells in combination with talimogene laherparepvec in immune checkpoint blockade refractory advanced melanoma patients: a phase I clinical trial

BackgroundIntratumoral (IT) myeloid dendritic cells (myDCs) play a pivotal role in initiating antitumor immune responses and relicensing of anti-tumor cytotoxic T lymphocytes within the tumor microenvironment. Talimogene laherparepvec (T-VEC) induces...

Precisely Targeted Nano-Controller of PD-L1 Level for Non-Small Cell Lung Cancer Spinal Metastasis Immunotherapy.

Although immune checkpoint inhibitors (ICIs) have been widely applied to treat non-small cell lung cancer (NSCLC), a significant proportion of patients, especially those with spinal metastasis (NSCLC-SM), are insensitive to anti-programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) ICIs. A drug delivery nano-controller of PD-L1 that targets NSCLC-SM can solve this problem, however, none have been developed to date. In this study, it is shown that integrin β3 (β3-int) is strongly upregulated in NSCLC-SM. Its inhibitor RGDyK promotes PD-L1 ubiquitination, indicating the potential application of RGDyK as a new PD-L1 inhibitor in nano-controller and a targeting peptide for NSCLC-SM treatment. According to the synergistic effect of photodynamic therapy and ICIs on T-cell activation through the release of tumor antigens, RGDyK-modified and zinc protoporphyrin (ZnPP)-loaded mesoporous silicon nanoparticles (ZnPP@MSN-RGDyK) are fabricated. The ZnPP@MSN-RGDyK nanoparticles precisely target β3-int to inhibit PD-L1, exhibiting high photodynamic therapy efficiency, and excellent immunotherapeutic effects in an NSCLC-SM mouse model. Collectively, the findings indicate that ZnPP@MSN-RGDyK is a promising immunotherapeutic agent for treating NSCLC-SM.

Rationally Designed Heptamethine Cyanine Photosensitizers that Amplify Tumor‐Specific Endoplasmic Reticulum Stress and Boost Antitumor Immunity (Small 34/2022)

Cancer Phototherapy The endoplasmic reticulum (ER) plays an important role in protein synthesis, processing and secretion. ER-targeting phototherapy significantly amplifies ER stress, promotes tumor antigen release, and elicits a robust immunogenic cell death. In article number 2202728 by Weidong Wang, Junping Wang, Shenglin Luo, and co-workers, a small molecular heptamethine cyanine photosensitizer with binitro-substituted benzenesulfonamide (ER-Cy-poNO2) is designed and synthesized for tumor photodynamic therapy/photothermal therapy/immunotherapy by targeting the ER.

Targeting Tumor Acidosis and Regulatory T Cells Unmasks Anti-Metastatic Potential of Local Tumor Ablation in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is an immunologically heterogenous disease that lacks clinically actionable targets and is more likely to progress to metastatic disease than other types of breast cancer. Tumor ablation has been used to increase response rates to checkpoint inhibitors, which remain low for TNBC patients. We hypothesized that tumor ablation could produce an anti-tumor response without using checkpoint inhibitors if immunosuppression (i.e., Tregs, tumor acidosis) was subdued. Tumors were primed with sodium bicarbonate (200 mM p.o.) to reduce tumor acidosis and low-dose cyclophosphamide (100–200 mg/kg i.p.) to deplete regulatory T cells, as has been shown independently in previous studies. A novel injectable ablative was then used to necrose the tumor, release tumor antigens, and initiate an immune event that could create an abscopal effect. This combination of bicarbonate, cyclophosphamide, and ablation, called “BiCyclA”, was tested in three syngeneic models of TNBC: E0771 (C57BL/6), 67NR (BALB/c), and 4T1-Luc (BALB/c). In E0771 and 67NR, BiCyclA therapy significantly reduced tumor growth and cured 5/7 and 6/10 mice 50 days after treatment respectively. In the metastatic 4T1-Luc tumors, for which surgery and checkpoint inhibitors fail, BiCyclA cured 5/10 mice of primary tumors and lung metastases. Notably, CD4+ and CD8+ T cells were found to be crucial for the anti-metastatic response, and cured mice were able to resist tumor rechallenge, suggesting production of immune memory. Reduction of tumor acidity and regulatory T cells with ablation is a simple yet effective therapy for local and systemic tumor control with broad applicability as it is not limited by expensive supplies.

Combination approaches in hepatocellular carcinoma: How systemic treatment can benefit candidates to locoregional modalities.

The management of hepatocellular carcinoma (HCC) is challenging because most patients have underlying cirrhosis, and the treatment provides, historically, a limited impact on the natural history of patients with advanced-stage disease. Additionally, recurrence rates are high for those patients who receive local and locoregional modalities, such as surgical (resection and transplantation) or image-guided (ablation and intra-arterial) therapies. Translational research has led to new concepts that are reshaping the current clinical practice. Substantial advancements were achieved in the understanding of the hallmarks that drive hepatocarcinogenesis. This has primed a successful incorporation of novel agents with different targets, such as anti-angiogenic drugs, targeted-therapies, and immune-checkpoint inhibitors. Although clinical trials have proven efficacy of systemic agents in advanced stage disease, there is no conclusive evidence to support their use in combination with loco-regional therapy. While novel local modalities are being incorporated (e.g., radioembolization, microwave ablation, and irreversible electroporation), emerging data indicate that locoregional treatments may induce tumor microenvironment changes, such as hyperexpression of growth factors, release of tumor antigens, infiltration of cytotoxic lymphocytes, and modulation of adaptative and innate immune response. Past trials that evaluated the use of antiangiogenic drugs in the adjuvant setting after ablation or chemoembolization fail to demonstrate a substantial improvement. Current efforts are directed to investigate the role of immunotherapy-based regimens in this context. The present review aims to describe the current landscape of systemic and locoregional treatments for HCC, present evidence to support combination approaches, and address future perspectives.

Hollow Aluminum Hydroxide Modified Silica Nanoadjuvants with Amplified Immunotherapy Effects through Immunogenic Cell Death Induction and Antigen Release.

In spite of the widespread application of vaccine adjuvants in various preventive vaccines at present, the existing adjuvants are still hindered by weak cellular immunity responses in therapeutic cancer vaccines. Herein, a hollow silica nanoadjuvant containing aluminum hydroxide spikes on the surface (SiAl) is synthesized for the co-loading of chemotherapeutic drug doxorubicin (Dox) and tumor fragment (TF) as tumor antigens (SiAl@Dox@TF). The obtained nanovaccines show significantly elevated anti-tumor immunity responses thanks to silica and aluminum-based composite nanoadjuvant-mediated tumor antigen release and Dox-induced immunogenic cell death (ICD). In addition, the highest frequencies of dendritic cells (DCs), CD4+ T cells, CD8+ T cells, and memory T cells as well as the best mice breast cancer (4T1) tumor growth inhibitory are also observed in SiAl@Dox@TF group, indicating favorable potential of SiAl nanoadjuvants for further applications. This work is believed to provide inspiration for the design of new-style nanoadjuvants and adjuvant-based cancer vaccines.

Rationally Designed Heptamethine Cyanine Photosensitizers that Amplify Tumor-Specific Endoplasmic Reticulum Stress and Boost Antitumor Immunity.

Cancer phototherapy activates immunogenic cell death (ICD) and elicits a systemic antitumor immune response, which is an emerging approach for tumor treatment. Most available photosensitizers require a combination of immune adjuvants or checkpoint inhibitors to trigger antitumor immunity because of the immunosuppressive tumor microenvironment and the limited phototherapeutic effect. A class of tumor-targeting heptamethine cyanine photosensitizers modified with an endoplasmic reticulum (ER)-targeting group (benzenesulfonamide) are synthesized. Phototherapy of tumor cells markedly amplifies ER stress and promotes tumor antigen release, as the ER is required for protein synthesis, secretion, and transport. More importantly, different electron-donating or -withdrawing substitutions are introduced into benzenesulfonamide to modulate the nonradiative decay pathways through intramolecular charge transfer, including singlet-triplet intersystem crossing (photodynamic effect) and internal thermal conversion (photothermal effect). Thus, a heptamethine cyanine photosensitizer containing a binitro-substituted benzenesulfonamide (ER-Cy-poNO2 ) is identified that preferentially accumulates in the ER of tumor cells. It significantly enhances the phototherapeutic effect by inducing excessive ER stress and robust ICD. Consequently, this small molecular photosensitizer triggers a sufficient antitumor immune response and effectively suppresses the growth of both primary and distant metastatic tumors, whereas no apparent toxicity is observed. This heptamethine cyanine photosensitizer has the potential to enhance cancer-targeted immunotherapy.