Targeting Tumor Microenvironment Research Articles

A Comprehensive Exploration of Agents Targeting Tumor Microenvironment: Challenges and Future Perspectives.

The tumor microenvironment (TME) encompasses the complex and diverse surroundings in which tumors arise. Emerging insights highlight the TME's critical role in tumor development, progression, metastasis, and treatment response. Consequently, the TME has attracted significant research and clinical interest, leading to the identification of numerous novel therapeutic targets. Advances in molecular technologies now enable detailed genomic and transcriptional analysis of cancer cells and the TME and the integration of microenvironmental data to the tumor genomic landscape. This comprehensive review discusses current progress in targeting the TME for drug development, addressing associated challenges, strategies for modulating the pro-tumor microenvironment, and the discovery of new targets.

From defense to offense: antimicrobial peptides as promising therapeutics for cancer.

Antimicrobial peptides (AMPs), naturally occurring components of innate immunity, are emerging as a promising new class of anticancer agents. This review explores the potential of AMPs as a novel class of anticancer agents. AMPs, naturally occurring peptides with broad-spectrum antimicrobial activity, exhibit several characteristics that make them attractive candidates for cancer therapy, including selectivity for cancer cells, broad-spectrum activity, and immunomodulatory effects. Analysis of a dataset of AMPs with anticancer activity reveals that their effectiveness is influenced by various structural properties, including net charge, length, Boman index, and hydrophobicity. These properties contribute to their ability to target and disrupt cancer cell membranes, interfere with intracellular processes, and modulate the immune response. The review highlights the promising potential of AMPs as a new frontier in cancer treatment, offering hope for more effective and less toxic therapies. AMPs demonstrate promising potential in cancer therapy through multiple mechanisms, including direct cytotoxicity, immune response modulation, and targeting of the tumor microenvironment, as evidenced by extensive preclinical studies in animal models showing tumor regression, metastasis inhibition, and improved survival rates. AMPs show significant potential as cancer therapeutics through their direct cytotoxicity, immune response modulation, and tumor microenvironment targeting, with promising results from preclinical studies and early-phase clinical trials. Future research should focus on optimizing AMP properties, developing novel delivery strategies, and exploring synergistic combination therapies to fully realize their potential as effective cancer treatments, while addressing challenges related to stability, delivery, and potential toxicity.

The Therapeutic Potential of Targeting Tumor Microenvironment and Modulation of Immunotherapy in Gastrointestinal Cancer.

Immunotherapy, as a novel treatment approach for various disorders, including cancers, is designed to either stimulate or suppress the immune system with high speci-ficity. The recent achievements of this therapy in clinical trials are set to transform tradi-tional treatment methods. Furthermore, it holds promise for enhancing the survival rates of patients suffering from both metastatic cancers and primary stages. Gastrointestinal Cancers (GI) account for 26% of global incidence and 35% of worldwide deaths. Treat-ment can be carried out using targeted immunotherapy in these cancers. If the tiers are superior, improvement could require more enterprise. On account that the function of immunotherapy in GI has been so promising, solely in sufferers with severe metastatic levels, within the literature, the immune checkpoint inhibitors in cancer immunotherapy of GI cancers, chimeric antigen receptor T-cell (vehicle-T), modulators of the tumor mi-croenvironment, and drug resistance mechanisms in immunotherapy as an effective treatment approach to GI cancers along with colon, pancreas, gastric, and esophageal cancers have been addressed. This review provides an overview of FDA-approved im-munotherapy drugs and ongoing preclinical developments. Additionally, we offer in-sights into the future of immunotherapy for GI cancer patients, addressing the associated challenges.

Lymphoma cell-driven IL-16 is expressed in activated B-cell-like diffuse large Bcell lymphomas and regulates the pro-tumor microenvironment.

The activated B-cell-like subtype of diffuse large B-cell lymphoma (ABC-DLBCL) displays a worse outcome than the germinal center B-cell-like subtype (GCB-DLBCL). Currently, targeting tumor microenvironment (TME) is the promising approach to cure DLBCL with profound molecular heterogeneity, however, the factors affecting the tumor-promoting TME of ABCDLBCL are elusive. Here, cytokine interleukin-16 (IL-16) is expressed in tumor cells of ABCDLBCL and secreted by the cleavage of active caspase-3. The serum IL-16 levels are not only a sensitive marker of treatment response but also positively correlated with unfavorable prognosis in DLBCL patients. While IL-16 shows few direct promotional effects on tumor cell growth in vitro, its bioactive form significantly promotes tumor progression in vivo. Mechanically, IL-16 increases the infiltration of macrophages by the chemotaxis of CD4+ monocytes in the TME enhancing angiogenesis, and the expression of cytokine IL-6 and IL-10, as well as decreasing T cell infiltration to accelerate tumor progression. This study demonstrates that IL-16 exerts a novel role in coordinating the bidirectional interactions between tumor progression and the TME. IMM0306, a fusion protein of CD20 mAb with the CD47 binding domain of SIRPα, reverses the tumorpromoting effects of IL-16,which provides new insight into treatment strategy in ABC-DLBCL.

Au@Pd nanozyme-mediated catalytic therapy: a novel strategy for targeting tumor microenvironment in cancer treatment

BackgroundBreast cancer, with its high morbidity and mortality rates, is a significant global health burden. Traditional treatments—surgery, chemotherapy, and radiotherapy—are widely used but come with drawbacks such as recurrence, metastasis, and significant side effects, including damage to healthy tissues. To address these limitations, new therapeutic strategies are being developed. Peroxidases (POD) can catalyze excess H2O2 in the tumor microenvironment to generate reactive oxygen species (ROS), which induce cancer cell apoptosis by disrupting redox homeostasis and modulating apoptosis-related proteins. However, natural enzymes face challenges like poor stability, high cost, and sensitivity to environmental conditions, limiting their application in breast cancer treatment. Nanozymes, nanomaterials with enzyme-like activity, offer a promising alternative by overcoming these limitations.MethodsIn this study, we successfully prepared Au@Pd nanozymes with peroxidase activity by depositing metallic Pd on Au nanoparticles (Au NPs) synthesized using a trisodium citrate reduction method and ascorbic acid reduction. The in vitro validation was conducted through a series of experiments, including ROS detection, flow cytometry, CCK-8 assay, DNA damage assessment, live/dead cell staining, Western blot (WB), and qPCR. Tumor treatment was performed via tail vein injection of the drug, followed by HE staining of the treated tissues and biochemical analysis of the blood.ResultsAu@Pd nanozymes can effectively accumulate at the tumor site through the EPR effect and exert peroxidase-like activity, catalyzing the excess H2O2 in the tumor microenvironment to produce ROS. This triggers apoptosis pathways and DNA damage, leading to the downregulation of the anti-apoptotic protein Bcl-2, upregulation of the pro-apoptotic protein Bax, and induction of apoptosis-related genes, demonstrating strong anti-tumor effects.ConclusionsThis study developed an efficient nanozyme-mediated catalytic therapy strategy targeting the tumor microenvironment for the treatment of breast cancer cells.

Leveraging single-cell RNA-seq for uncovering naïve B cells associated with better prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China; however, the immune microenvironment of HCC has not been clarified so far. Here, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC tumor microenvironment (TME). Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for HCC.

Precision Targeting Strategies in Pancreatic Cancer: The Role of Tumor Microenvironment.

Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing.

Targeting tumor microenvironment with photodynamic nanomedicine.

Photodynamic therapy (PDT) is approved for the treatment of certain cancers and precancer lesions. While early Photosensitizers (PS) have found their way to the clinic, research in the last two decades has led to the development of third-generation PS, including photodynamic nanomedicine for improved tumor delivery and minimal systemic or phototoxicity. In terms of nanoparticle design for PDT, we are witnessing a shift from passive to active delivery for improved outcomes with reduced PS dosage. Tumor microenvironment (TME) comprises of a complex and dynamic landscape with myriad potential targets for photodynamic nanocarriers that are surface-modified with ligands. Herein, we review ways to improvise PDT by actively targeting nanoparticles (NPs) to intracellular organelles such as mitochondria or lysosomes and so forth, overcoming the limitations caused by PDT-induced hypoxia, disrupting the blood vascular networks in tumor tissues-vascular targeted PDT (VTP) and targeting immune cells for photoimmunotherapy. We propose that a synergistic outlook will help to address challenges such as deep-seated tumors, metastasis, or relapse and would lead to robust PDT response in patients.

21 Unconventional mechanisms of action and resistance to rapalogs in renal cancer

Abstract Background Clear cell renal cell carcinoma (ccRCC) is a prevalent cancer type in the United States driven by inactivation of the von Hippel-Lindau (VHL) gene and with frequent hyperactivation of mammalian target of rapamycin complex 1 (mTORC1). Multiple drugs have been developed to target VEGF/VEGFR2 and mTORC1 for advanced RCC treatment. Two specific mTORC1 inhibitors, temsirolimus and everolimus (known as rapalogs), are FDA-approved for the treatment of RCC but their clinical efficacy is hindered by the emergence of resistance. Methods To study the development of rapalog resistance in RCC, we utilized patient-derived tumorgrafts (TGs) implanted in immunocompromised mice and treated the mice with rapamycin for prolonged periods to generate resistance. Resistance was studied by transplanting resistant tumors into additional cohorts of mice and establishing primary cultures. The impact of rapamycin on tumor growth and mTORC1 activity in both tumor and stromal cells was assessed using molecular techniques. To dissect the role of the tumor microenvironment (TME), we generated genetically engineered immunocompromised recipient mice with an mTOR inhibitor resistance mutation (S2035T). Coculture experiments were performed to further explore the interplay. Results Prolonged rapamycin treatment resulted in the development of resistance in TGs. Notably, this occurred despite persistent inhibition of mTORC1 in tumor cells. Resistance was transient and lost with subsequent transplantation and in cell culture. Surprisingly, resistance was accompanied by mTORC1 reactivation in the TME, specifically in cancer associated fibroblasts. Introducing an mTOR resistance mutation (S2035T) into recipient mice was sufficient to cause resistance. Co-culture experiments with fibroblasts further demonstrated that rapamycin-resistant mutant fibroblasts conferred resistance in tumor cells even in the absence of mTORC1 activity. Conclusions This study uncovers a critical role of the TME, in mediating the response and resistance to rapalogs in RCC. Our data show that inhibition of mTORC1 in non-tumor cells is essential for the anti-tumor activity of rapalogs. These findings shed light on why mTOR mutations are rarely observed in resistant RCC patients and highlight the significance of the TME in modulating drug response and resistance. Moreover, our study emphasizes the potential of targeting TME cells as a therapeutic strategy in RCC and possibly other cancers. DOD CDMRP Funding: yes

Hybrid nanopotentiators with dual cascade amplification for glioma combined interventional therapy

Glioma is an aggressive malignant brain tumor with a very poor prognosis for survival. The poor tumor targeting efficiency and tumor microenvironment penetration barrier also as troubles inhibited the effective glioma chemotherapy. Here, we design a core-shell structure cascade amplified hybrid catalytic nanopotentiators CFpAD with DM1 encapsulated to overcome the glioma therapeutic obstacles. NIR laser-based BBB penetrating enhances the tumor accumulation of CFpAD. When CFpAD, as the cascade amplified drug, is treated on the cancer cells, the bomb-like CFpAD releases gold nanoparticles as glucose oxidase (GOx) and ferric oxide nanoparticles (FNPs) as peroxides (POx) after blasting, producing ROS via a cascade amplification for tumor cell apoptosis. Gold nanoparticles can rest CAFs and reduce ECM secretion, achieving deep penetration of CFpAD. Moreover, CFpAD also cuts off the nutritional supply of the tumor, reduces the pH value, and releases free radicals to destroy the cancer. The glioma cell viability was significantly decreased through DNA damage and ROS aggregation due to the DM1-based chemotherapy synergistically combined with interventional photothermal therapy (IPTT) and radiotherapy (RT). This domino cascade amplified loop, combined with starvation therapy with IPTT and RT, has good tumor penetration and outstanding antitumor efficacy, and is a promising glioma treatment system.

The activity and safety of icaritin for patients with unresectable HCC: A real world, retrospective study.

e16181 Background: Primary liver cancer is a major health burden globally, ranking sixth in incidence and third in mortality among all cancers[1]. Over the past 5 years, immune checkpoint inhibitors (ICIs) and multi-targeted tyrosine-kinase inhibitors have emerged as new treatment options for advanced hepatocellular carcinoma[2–4]. Nevertheless, only a small subset of patients with hepatocellular carcinoma derive a response to ICI monotherapy. Icaritin, a target tumor micro-environment(TME) modulating compound, which interacts with MyD88/IkB kinase-a (IKK)[5], inhibiting the TNF-a-induced IKK and nuclear factor-κB (NF-kB) signaling pathways and blocking PD-L1 expression in HBV-related HCC[6-9] and has been approved in China for the treatment of first-line advanced HCC. Icaritin phase III study previously reported at 2021 ASCO, we therefore investigated the efficacy of icaritin in patients with unresectable stage IIA-IIIB (CNLC stage) HCC in a real-world setting. Methods: This multi-center, retrospective study, conducted between May 2022 and Nov 2023. We retrospectively collected medical records of patients (pts) with unresectable IIA-IIIB (CNLC stage) HCC who received icaritin monotherapy (mono-group) or icaritin combined with PD-1/L1 and/or anti-VEGF therapy (combination group) as first line therapy. The primary endpoints were progression free survival (PFS); Secondary endpoints included overall survival (OS) rate, objective response rate (ORR) by RECIST v1.1, and safety. Results: Patients characteristics: 49 pts were eligible for inclusion with median age of 60.7 years old (range 18.0-89.0), 91.8% were ECOG PS 0-1, 86.5% had HBV infection, 79.6% were stage III and 48.9% were AFP>400 ng/ml. 33 pts administrated with combination therapy, other 16 pts’ regimen was icaritin monotherapy. Efficacy: As of the data cutoff for the preliminary analysis of progression free survival (Nov 30, 2023), the median follow-up was 11.17 months (95%CI 6.74–12.12). The ORR for the combination group was 6.06%, and 12.50% for the mono-group, the mPFS was 8.94(95%CI 6.90~9.76) and 5.52 (2.92~NE) for each group. The mOS was not reached for both group, the 6 and 12-months OS rates were 91.00% and 73.67% respectively. Safety: For the safety information, most of TRAEs were grade 1 or 2. No serious AEs were observed. Conclusions: This real-world retrospective study revealed that icaritin monotherapy and icaritin-based combination therapy are promising therapeutic options for unresectable HCC in China. Clinical trial information: ChiCTR2300074565.

Hemay181: A novel SDC (sugar linked drug conjugate) for solid tumors targeting tumor microenvironment.

e15006 Background: Hemay181 is a novel broad-spectrum conjugated cytotoxic drug for treating advanced solid tumours. The drug exerts its inhibitory effect on tumour growth by releasing cytotoxic drug SN-38 in tumour tissues via β-glucuronidase (βGU) metabolism to inhibit the activity of topoisomerase I (TOP1). The water solubility of Hemay181 is increased > 5000-fold compared to SN-38. Hemay181 also binds to plasma albumin to form a macromolecular drug transporter, significantly improving the drug's pharmacokinetics. In addition, βGU has low activity in normal tissues, localised to the lysosomes, but is highly expressed in the hypoxic tumour microenvironment. Methods: In vitro and In Vivo studies showed Hemay181 inhibited growth in 29 human tumour cell lines and 16 human tumor Xenograft models, including colorectal cancer, gastric cancer, triple-negative breast cancer, head and neck cancer, pancreatic cancer, lung cancer, prostate cancer and melanoma. Results: In the absence of βGU, Hemay181 showed significantly weaker inhibitory activity than Hemay181+βGU or no significant inhibitory activity. In these In vitro studies with the addition of βGU, the activity was similar to SN-38, ranging from 3.9 nM to 159 nM. Hemay181 showed tumor selectivity with low activity against two normal human cell lines. The IC50 values of Hemay181 against Chang liver (normal liver cells) and MRC 5 (embryonic lung cells) were 318 nM and 14566 nM under non-enzymatic digestion conditions. In vivo, Hemay181 had significant inhibitory effects on the growth of human colorectal cancer, pancreatic cancer, head and neck cancer, triple-negative breast cancer, lung cancer, liver cancer, ovarian cancer and gastric cancer tumour models. The lowest effective dose of Hemay181 was 1.875mg/kg in the human colon cancer HCT116 model. Within the dose range of 3.75~60 mg/kg, the highest inhibitory rate of the above different tumour models could reach more than 90%. Hemay181 significantly reduced tumour volume compared to irinotecan, which only slowed the tumour growth rates. There was no significant decrease in the body weight of Hemay181 in these studies. In the colon cancer PDX model (CR0029) (30mg/kg), the tumour inhibition rate (TGI) was 78%. At 60mg/kg, in triple-negative breast cancer (BR1458) and non-small cell lung cancer (LU3075) PDX models, a TGI was 97% and 98%, respectively. At 60mg/kg, there was a significant tumour suppressive effect on larger tumours treated with irinotecan, with a reduction of tumour volume. In vitro , 1 μM Hemay181 is stable in CD1 mouse and SD rat plasma, with a minor degree of metabolism in beagle dog, cynomolgus monkey and human plasma. Conclusions: In summary, the novel broad-spectrum anti-tumour drug Hemay181 has the characteristics of high water solubility, tumour-targeting ability, low toxicity and side effects on normal tissues. It is under evaluation in ongoing clinical studies.

An artificial signaling pathway primitive-based intelligent biomimetic nanoenzymes carrier platform for precise treatment of Her2 (+) tumors

In tumor treatment, the deposition of nanoenzymes in normal tissues and cause potential side effects are unavoidable. Here, we designed an intelligent biomimetic nanoenzymes carrier platform (MSCintelligent) that endows the carrier platform with “wisdom” by introducing Affibody-Notch(core)-VP64-GAL4/UAS-HSV-TK artificial signal pathways to mesenchymal stem cells (MSCs). This intelligent nanoenzymes carrier platform is distinguished from the traditional targeting tumor microenvironment or enhancing affinity with tumor, which endue MSCintelligent with tumor signal recognition capacity, so that MSCintelligent can autonomously distinguish tumor from normal tissue cells and feedback edited instructions. In this study, MSCintelligent can convert tumor signals into HSV-TK instructions through artificial signal pathway after recognizing Her2 (+) tumor. Subsequently, the synthesized HSV-TK can rupture MSCintelligent under the mediation of ganciclovir, and release the preloaded Cu/Fe nanocrystal clusters to kill the tumor accurately. Meanwhile, MSCintelligent without recognizing tumors will not initiate the HSV-TK instructions, thus being unresponsive to GCV and blocking the release of nanoenzymes in normal tissues. Consequently, MSCintelligent is the first intelligent biomimetic nanoenzymes carrier platform, which represents a new biomimetic nanoenzymes targeting mode.

Single-cell transcriptomics reveals the aggressive landscape of high-grade serous carcinoma and therapeutic targets in tumor microenvironment

High-grade serous carcinoma (HGSC) is characterized by early abdominal metastasis, leading to a dismal prognosis. In this study, we conducted single-cell RNA sequencing on 109,573 cells from 34 tumor samples of 18 HGSC patients, including both primary tumors and their metastatic sites. Our analysis revealed a distinct S100A9+ tumor cell subtype present in both primary and metastatic sites, strongly associated with poor overall survival. This subtype exhibited high expression of S100A8, S100A9, ADGRF1, CEACAM6, CST6, NDRG2, MUC4, PI3, SDC1, and C15orf48. Individual knockdown of these ten marker genes, validated through in vitro and in vivo models, significantly inhibited ovarian cancer growth and invasion. Around S100A9+ tumor cells, a population of HK2+_CAF was identified, characterized by activated glycolysis metabolism, correlating with shorter overall survival in patients. Notably, similar to CAFs, immunosuppressive tumor-associated macrophage (TAM) subtypes underwent glycolipid metabolism reprogramming via PPARgamma regulation, promoting tumor metastasis. These findings shed light on the mechanisms driving the aggressiveness of HGSC, offering crucial insights for the development of novel therapeutic targets against this formidable cancer.

Biomimetic MDSCs membrane coated black phosphorus nanosheets system for photothermal therapy/photodynamic therapy synergized chemotherapy of cancer

Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.

Abstract 7039: Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma

Abstract The immune cell types as well as tumor microenvironment (TME) status may influence prognosis, metastasis, tumor progression, and clinical response to immunotherapies for cancer. Hepatocellular carcinoma (HCC) is a typical highly heterogeneous solid tumor with high morbidity and mortality worldwide, especially in China, however, the immune microenvironment of HCC, especially which caused by cancerogenic substance has not been clarified so far. In this study, we employed single-cell RNA sequencing (scRNA-seq) on diethylnitrosamine (DEN)-induced mouse HCC model to dissect the immune cell dynamics during tumorigenesis. Our findings reveal distinct immune profiles in both precancerous and cancerous lesions, indicating early tumor-associated immunological alterations. Notably, specific T and B cell subpopulations are preferentially enriched in the HCC TME. Furthermore, we identified a subpopulation of naïve B cells with high CD83 expression, correlating with improved prognosis in human HCC. These signature genes were validated in The Cancer Genome Atlas (TCGA) HCC RNA-seq dataset. Moreover, cell interaction analysis revealed that subpopulations of B cells in both mouse and human samples are activated and may potentially contribute to oncogenic processes. In summary, our study provides insights into the dynamic immune microenvironment and cellular networks in HCC pathogenesis, with a specific emphasis on naïve B cells. These findings emphasize the significance of targeting TME in HCC patients to prevent HCC pathological progression, which may give a new perspective on the therapeutics for the HCC. Citation Format: Jian He. Leveraging single cell RNA-seq for uncovering immune landscape of hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7039.

Abstract 3735: Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy

Abstract Successful cancer-immunotherapy need to address three critical factors: a) Relieving the immuno-suppressive tumor microenvironment (TME) b) expanding antigen specific, functionally avid effector T cells, c) triggering systemic immunity with a balanced innate-adaptive response for continued effector cell-feeder supply-chain and memory generation. Combinatorial engagement of such multi-elemental components demands smart, engineered immunotherapy systems compared to conventional vaccines. Here, we report an injectable Nano-Immuno-Gel (NIG) that can neutralize immunosuppressive components (e.g., myeloid derived suppressor cells (MDSCs), M2 macrophages (Mϕ) in TME, together with generating strong effector T cells by nano-vaccination, and sustained release of cytokines to enhance systemic immunity against tumor. In a proof-of-concept study, we show that sustained-release of myeloid-suppressive drug from NIG depot efficiently inhibited MDSCs and M2 Mϕ, not only in TME, but also in the circulation and in peripheral systems, thus creating a conducive, hot TME infiltrated with CD8 effector cells. Follow-up antigen vaccination with novel nano-adjuvant enhanced DC-T cell engagement and sustained IL15 release from NIG provided systemic NK/T cell activation, rendering significant control of the tumor growth. Our data demonstrate the potential of rationally engineered multi-functional nano-immuno-gels (NIG) to combine sequential neutralization of the suppressive TME, antigen vaccination, and concurrent systemic immune activation for highly effective combinatorial cancer immunotherapy. Citation Format: Anjali Kozhissery Sunilkumar, Margaux Salvi, Saira Nujoom Mohammed, Zahara Thaivalappil Zakkariya, Alejandra Gomez Cadena, Shalin Chappan, Sreedevi Panachithanathu Radhakrishnan, Maneesh Manohar, Pavithran Keechilat, Shantikumar Nair, Pedro Romero, Camilla Jandus, Manzoor Koyakutty. Combinatorial targeting of tumor-microenvironment together with antigen vaccination using innovative nano-immuno-gel for enhanced cancer-immunotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3735.

Tackling suppressive cancer microenvironment by NARF-derived immune modulatory vaccine and its validation using simulation strategies

Introduction: Targeting tumor microenvironment is beneficial and present an ideal setting for the development of futuristic immunotherapy. Here, we make use of Nuclear prelamin A recognition factor (NARF), a protein linked to the coactivation of transcriptional regulators in human breast cancer stem cells (CSC) in our investigation.Methods: In this study, we initially computed the epitope regions possessing the ability to stimulate both T and B cells within the NARF protein. These identified epitope areas were fused with an adjuvant such as RpfB and RpfE as well as linkers like AAY, GPGPG, KK, and EAAAK. The constructed vaccine was further characterized by assessing its physicochemical properties and population coverage. The potential interactions of the designed vaccine with different toll-like receptors were examined by a sequence of computational studies. Of note, docking study were employed to understand its mechanism of action. Molecular dynamics and immune simulation studies were conducted to comprehend more into their structural stability and immune responses. The resultant vaccine was back-translated, codon-optimised and introduced into pET-28 (+) vector.Results and discussion: We hypothesize from the results that the designed NARF protein-based vaccine in our analysis could effectively provoke the immune responses in the target organism through TLR-7 binding and promotes MHC class-II mediated antigen presentation. Indeed, comprehensive evaluations conducted in both in vitro and in vivo settings are imperative to substantiate the safety and efficacy of the developed vaccine.

The golden key to open mystery boxes of SMARCA4-deficient undifferentiated thoracic tumor: focusing immunotherapy, tumor microenvironment and epigenetic regulation.

SMARCA4-deficient undifferentiated thoracic tumor is extremely invasive. This tumor with poor prognosis is easily confused with SMARCA4-deficent non-small cell lung cancer or sarcoma. Standard and efficient treatment has not been established. In this review, we summarized the etiology, pathogenesis and diagnosis, reviewed current and proposed innovative strategies for treatment and improving prognosis. Immunotherapy, targeting tumor microenvironment and epigenetic regulator have improved the prognosis of cancer patients. We summarized clinicopathological features and immunotherapy strategies and analyzed the progression-free survival (PFS) and overall survival (OS) of patients with SMARCA4-UT who received immune checkpoint inhibitors (ICIs). In addition, we proposed the feasibility of epigenetic regulation in the treatment of SMARCA4-UT. To our knowledge, this is the first review that aims to explore innovative strategies for targeting tumor microenvironment and epigenetic regulation and identify potential benefit population for immunotherapy to improve the prognosis.

Advances in targeting tumor microenvironment for immunotherapy.

The tumor microenvironment (TME) provides essential conditions for the occurrence, invasion, and spread of cancer cells. Initial research has uncovered immunosuppressive properties of the TME, which include low oxygen levels (hypoxia), acidic conditions (low pH), increased interstitial pressure, heightened permeability of tumor vasculature, and an inflammatory microenvironment. The presence of various immunosuppressive components leads to immune evasion and affects immunotherapy efficacy. This indicates the potential value of targeting the TME in cancer immunotherapy. Therefore, TME remodeling has become an effective method for enhancing host immune responses against tumors. In this study, we elaborate on the characteristics and composition of the TME and how it weakens immune surveillance and summarize targeted therapeutic strategies for regulating the TME.