Target For Tumor Therapy Research Articles

A Facile Approach To Develop Ion Pair Micelles Satellited Freshly Derived Neutrophils For Targeted Tumor Therapy.

Immune cells show enormous potential for targeted nanoparticle delivery due to their intrinsic tumor-homing skills. However, the immune cells can internalize the nanoparticles, leading to cellular functional impairments, degradation of the nanoparticles, and delayed release of drugs from the immune cells. To address these issues, this study introduces an approach for the synthesis of freshly derived neutrophils (NUs)-based nanocarriers system where the NUs are surfaced by dialdehyde alginate-coated self-assembled micelles loaded with mitoxantrone (MIT) and indocyanine green (ICG) (i.e., dA(MI@IPM)s) for stimuli-responsive tumor-targeted therapy. Here, the dA(MI@IPM)s are not internalized by the NUs, but they are anchored on the membrane of the NUs via distearoylphosphatidylethanolamine-polyethylene glycol-polyethylenimine anchors. Owing to the natural recruitment ability of NUs to the tumor microenvironment, NUs-anchored dA(MI@IPM)s accumulation is higher at the tumor site than free dA(MI@IPM)s, where the dA(MI@IPM)s can readily detach from the NUs to get internalized in the tumor cells. The stimuli-responsive dA(MI@IPM)s disassembles inside the cancer cells upon near-infrared irradiation due to the photosensitizing effect of the loaded ICG, releasing MIT and significantly inhibiting tumor growth. This approach is simple and fast to prepare, opening up exciting possibilities for personalized cancer treatment using patient's autologous NUs.

Sequential self-assembly and release of a camptothecin prodrug for tumor-targeting therapy.

Chemotherapy is the most commonly used method to treat malignant tumors with a wide range of drugs. However, chemotherapeutic drugs are characterized by poor solubility, low stability and specificity, as well as drug resistance, which led to their limited bioavailability and severe adverse effects. Therefore, most researches focus on one or two strategies while a few researches focus on three strategies to improve the efficacy of drugs. Herein, we combined three strategies (targeted therapy, prodrug design and drug delivery) to exploit a self-assembled camptothecin (CPT) prodrug (CPT-SS-FFEYp-Biotin) for enhancing therapeutic efficacy and reducing side effects of CPT. CPT-SS-FFEYp-Biotin enters into tumor cells following the recognition between biotin and biotin receptors. Moreover, the over-expressed alkaline phosphatase (ALP) on cell membranes specifically dephosphorylates CPT-SS-FFEYp-Biotin to CPT-SS-FFEY-Biotin, which self-assembles into a CPT hydrogel with the local enrichment of CPT. Subsequently, excess glutathione (GSH) in tumor cells can reduce the disulfide bond of CPT-SS-FFEY-Biotin to slowly release CPT for sustained tumor therapy. Cell experiments demonstrated that CPT-SS-FFEYp-Biotin enhances therapeutic efficacy of CPT on tumor cells while being safer to normal cells than CPT. Moreover, CPT-SS-FFEYp-Biotin effectively improved anti-tumor treatment of CPT in vivo. We envision that the integration of these three strategies is helpful to exploit a variety of prodrugs for effective anti-tumor treatment in the future.

Tumor Microenvironment Responsive Key Nanomicelles for Effective Against Invasion and Metastasis in Ovarian Cancer Using Mice Model.

Ovarian cancer is difficult to detect in its early stages, and it has a high potential for invasion and metastasis, along with a high rate of recurrence. These factors contribute to the poor prognosis and reduced survival times for patients with this disease. The effectiveness of conventional chemoradiotherapy remains limited. Nano-particles, as a novel drug delivery system, have significant potential for improving therapeutic efficacy and overcoming these challenges. According to the high expression level of matrix metalloproteinase-2 (MMP-2) in the tumor microenvironment, MMP-2 responsive nano-particles (PVGLIG-MTX-D/T-NMs) containing docetaxel and triptolide were prepared by the thin-film dispersion method. The synergistic effect between docetaxel and triptolide was systematically investigated, the ratio of the two drugs was optimized, and the physicochemical properties of the nano-particles and their ability to inhibit ovarian cancer cell growth and metastasis were evaluated in vitro and in vivo. PVGLIG-MTX-D/T-NMs enhanced the targeting, stability, and bioavailability of the drug, while reducing the dose and toxicity. In addition, by regulating the expression levels of E-Cadherin, N-Cadherin, matrix metalloproteinases (MMPs), hypoxia-inducible factor 1-alpha (HIF-1α), and vascular endothelial growth factor (VEGF), it exhibited an inhibitory effect on epithelial-mesenchymal transformation (EMT) and tumor cell angiogenesis, and effectively inhibited the invasion and metastasis of ovarian cancer cells. PVGLIG-MTX-D/T-NMs achieved passive targeting of tumor sites by enhancing permeability and retention (EPR) effects. Subsequently, the uptake of the drug by tumor cells was enhanced by MMP-2 responsiveness and the modification of methotrexate targeting ligands. By regulating the expression levels of invasion- and metastasis-related proteins in tumor tissues, the nano-particles affected the EMT process, inhibited tumor angiogenesis, and suppressed the malignant potential of invasion and metastasis in ovarian cancer. These findings provided a new direction for further exploration of tumor-targeted therapy.

Peptide Nanocarriers for Targeted Delivery of Nucleic Acids for Cancer Therapy.

Peptides have been extensively studied in nanomedicine with great bioactivity and biocompatibility; however, their poor cell-membrane-penetrating properties and nonselectivity greatly limit their clinical applications. In this study, tumor-targeting therapy was achieved by modifying our previously developed efficient peptide vector with the cancer-targeting peptide RGD, enabling it to specifically target tumor cells with a high expression of RGD-binding receptors. B-cell lymphoma-2 antisense oligonucleotides were selected as the target model to validate the effectiveness of the delivery carriers. Results demonstrated that this delivery system can be efficiently and selectively taken up by RGD receptor-positive cells (αvβ3 integrin receptor), further inducing effective target gene knockdown. Overall, this system provided a promising strategy for the targeted delivery of nucleic acid drugs.

A Phthalimide-Functionalized Heptamethine Cyanine Dye for Tumor-Targeted Photothermal Therapy.

A phthalimide-functionalized heptamethine cyanine dye, named Ph790H, is used for targeted photothermal cancer therapy in vivo. We highlight that the chemical structure of Ph790H is newly designed and synthesized for the first time in this study. By possessing a rigid chloro-cyclohexenyl ring in the heptamethine cyanine backbone, the bifunctional near-infrared (NIR) fluorescent dye Ph790H can be preferentially accumulated in tumor without the need for additional targeting ligands, which is defined as the "structure-inherent tumor targeting" concept. The phototherapeutic effect of Ph790H is evaluated in HT-29 human colorectal cancer xenografts to be used as a cancer-targeting photothermal agent. The results reveal that the Ph790H shows enhanced tumor accumulation in HT-29 xenografts 48 h post-injection with a high tumor-to-background ratio. After determination of the optimal timing for photothermal therapy (PTT), the HT-29 tumor-possessing nude mice pretreated with Ph790H are subsequently irradiated with an 808 nm NIR laser for 5 min. The tumor-targeted PTT treatment can efficiently inhibit the tumor development compared with that of control groups. Moreover, no tumor regrowth or Ph790H-induced mortality occurs after the treatment of Ph790H and laser irradiation during a period of monitoring. Therefore, this work demonstrates that the bifunctional phototheranostic agent Ph790H can be utilized for targeted cancer imaging and fluorescence-guided phototherapy simultaneously.

Targeting APE1: Advancements in the Diagnosis and Treatment of Tumors.

With the emergence of the precision medicine era, targeting specific proteins has emerged as a pivotal breakthrough in tumor diagnosis and treatment. Apurinic/apyrimidinic Endonuclease 1 (APE1) is a multifunctional protein that plays a crucial role in DNA repair and cellular redox regulation. This article comprehensively explores the fundamental mechanisms of APE1 as a multifunctional enzyme in biology, with particular emphasis on its potential significance in disease diagnosis and strategies for tumor treatment. Firstly, this article meticulously analyzes the intricate biological functions of APE1 at a molecular level, establishing a solid theoretical foundation for subsequent research endeavors. In terms of diagnostic applications, the presence of APE1 can be detected in patient serum samples, biopsy tissues, and through cellular in situ testing. The precise detection methods enable changes in APE1 levels to serve as reliable biomarkers for predicting tumor occurrence, progression, and patient prognosis. Moreover, this article focuses on elucidating the potential role of APE1 in tumor treatment by exploring various inhibitors, including nucleic acid-based inhibitors and small molecule drug inhibitors categories, and revealing their unique advantages in disrupting DNA repair function and modulating oxidative-reduction activity. Finally, the article provides an outlook on future research directions for APE1 while acknowledging major technical difficulties and clinical challenges that need to be overcome despite its immense potential as a target for tumor therapy.

Ascorbate/methionine-based CH4 delivery nanomedicine for tumor-targeted therapy.

Methane (CH4) is identified to be an emerging anti-inflammation and anti-cancer molecule with high bio-safety, but the targeted delivery of CH4 is a thorny challenge. Herein, we propose a CH4 delivery strategy based on an intratumoral H2O2-triggered cascade reaction of ascorbic acid (AA)/methionine (Met), and have constructed a new nanomedicine (AMN) for tumor-targeted CH4 therapy. Encouragingly, AMN realizes the effective tumor-targeted delivery and intratumoral H2O2-responsive release of CH4, and exhibits significant anti-cancer effects and high bio-safety. Mechanistically, we have discovered that intratumoral released CH4 can not only induce the apoptosis of 4T1 tumor cells by inhibiting their mitochondrial metabolism, but also activate tumor immunotherapy by reprogramming tumor-associated macrophages (TAMs) phenotype (M2 to M1). The combination of the above anti-cancer pathways by virtue of tumor-targeted CH4 delivery makes contribution to outstanding anti-cancer efficacy of AMN. The proposed CH4 delivery strategy opens a new window for safe and effective tumor therapy.

Ferroptosis: A novel cell death modality as a synergistic therapeutic strategy with photodynamic therapy.

Although there has been significant progress in current comprehensive anticancer treatments centered on surgery, postoperative recurrence and tumor metastasis still significantly affect both prognosis and quality of life of the patient. Hence, the development of precisely targeted tumor therapies and exploration of immunotherapy represent additional strategies for tumor treatment. Photodynamic therapy (PDT) is a relatively safe treatment modality that not only induces multiple modes of tumor cell death but also mediates the secondary immunological responses against tumor resistance and metastasis. Ferroptosis, an iron-dependent type of programmed cell death characterized by accumulation of reactive oxygen species and lipid peroxidation products to lethal levels, has emerged as an attractive target trigger for tumor therapies. Recent research has revealed a close association between PDT and ferroptosis, suggesting that combining ferroptosis inducers with PDT could strengthen their synergistic anti-tumor efficiency. Here in this review, we discuss the rationale for combining PDT with ferroptosis inducers and highlight the progress of single-molecule photosensitizers to induce ferroptosis, as well as the applications of photosensitizers combined with other therapeutic drugs for collaborative therapy. Furthermore, given the current research dilemma, we propose potential therapeutic strategies to advance the combined usage of PDT and ferroptosis inducers, providing the basis and guidelines for prospective clinical translation and research directionality with regard to PDT.

Dynamic-Covalent Mesoporous Silica Nanohybrid with pH/ROS-Responsive Drug Release for Targeted Tumor Therapy.

Nanomedicine provides promising new methodologies for the treatment of tumors but still faces several limitations, including poor colloidal stability, uncontrollable drug release, and insufficient drug targeting. Herein, hyaluronic acid (HA) was used to modify the surface of mesoporous silica nanoparticles (MSNs) via a dynamic-covalent linker, phenylborate ester (PBAE), termed MA. The HA modifier provided enhanced colloidal stability to the hybrid nanoparticles. As expected, MA exhibited an improved biocompatibility and high potential for biomedical applications. Moreover, MA with a negatively charged surface effectively adsorbed the drug Doxorubicin (DOX) inside the carriers, ensuring minimal drug leakage. In an acidic and reactive oxygen species (ROS)-containing condition mimicking the tumor microenvironment, MA@DOX (MAD) continuously released its payloads, likely due to the cleavage of the pH/ROS-sensitive PBAE. Compared with free DOX, MAD had 2.2 times higher accessibility to tumor cells than free DOX. The favorable stability and cancer-selective drug release make this nanoformulation a promising platform for potent cancer treatment.

Study on antibody-conjugated drugs and targeted therapy for triple-negative breast cancer

Abstract. Statistics show that, second only to lung cancer, breast cancer is now the most common type of cancer worldwide. Compared to other forms of breast cancer, triple negative breast cancer (TNBC) has a worse prognosis, extensive metastases, and poor efficacy, making treatment more difficult. antibody-drug conjugates (ADCs), have become a hot topic in targeted tumor therapy research. Gosa tuzumab is the first drug approved for advanced TNBC treatment globally. However, challenges remain in the clinical use of ADCs, such as limited delivery of ADCs to target cells and suboptimal anti-tumor effects. This article analyzes targeted therapy methods and ADCs for TNBC, summarizes current market gosa tuzumab and ongoing clinical trials for ADCs drugs, providing a reference for further study on TNBC treatment with ADCs. Nevertheless, issues like drug resistance, adverse reactions and combination strategies with other chemotherapy inhibitors for TNBC treatment warrant further investigation in future clinical trials.

Bone marrow mesenchymal stem cell-derived exosomes improve cancer drug delivery in human cell lines and a mouse osteosarcoma model.

Osteosarcoma is the most common primary bone tumor. Patients require chemotherapy drugs with high-targeting ability and low off-target toxicity to improve their survival. Exosomes are biological vesicles that mediate long-distance communication between cells and naturally target their source sites. Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) naturally target bone tumor sites, suggesting their potential as effective anti-tumor therapy vectors. In this study, we evaluated the potential of BMSC-derived exosomes in targeting osteosarcoma and serving as a carrier for doxorubicin (DOX). We isolated exosomes from human BMSCs and synthesized hybrid exosomes (HEs) by fusing these exosomes with liposomes. These HEs were loaded with DOX to produce a novel drug, HE/DOX. We confirmed the successful synthesis of HE/DOX using fluorescence spectroscopy and estimated its size to be 151.1 ± 10.2 nm. HEs expressed the known exosomal proteins ALIX, CD63, and TSG101. Under acidic conditions similar to those observed in the tumor microenvironment, the drug release from HE/DOX was enhanced. In osteosarcoma cell lines and in a mouse osteosarcoma model, HE/DOX exhibited stronger tumor-inhibitory effects than free DOX. Our study demonstrates that BMSC-derived exosomes could effectively target osteosarcoma. Furthermore, HEs can serve as effective carriers of DOX, enabling the treatment of osteosarcoma. These findings highlight a promising direction for tumor-targeted therapy.

EXTH-16. UNBIASED DISCOVERY OF SYNERGISTIC VULNERABILITIES AGAINST GLIOBLASTOMA: AN INNOVATIVEIN VIVO CRISPR PROFILING PLATFORM TO UNLEASH THE POWER OF TUMOR-TARGETED CYTOKINE THERAPY

Abstract BACKGROUND Glioblastoma poses a formidable challenge due to its intricate intra- and intertumoral heterogeneities and its associated immunosuppressive milieu. The standards of care have limited activity, and no major advances have been made in decades. One promising avenue is tumor-targeted cytokine-based therapies, particularly L19-TNF, which is undergoing clinical trials in Europe and the US for patients with newly diagnosed and recurrent glioblastoma. However, there is still an opportunity to find safer and more tolerable combination partners to improve the efficacy of L19-TNF immunotherapy. To address this challenge, we employed a cutting-edge in vivo CRISPR screening approach to identify synergistic vulnerabilities with a focus on druggable targets. METHODS We systematically investigated the dependencies of tumor growth and key signaling pathways under the pressure of L19-TNF immunotherapy in the CT-2A orthotopic murine glioma model. We used an innovative in vivo CRISPR screening approach that enables timed sgRNA activation to mitigate off-target effects and overcome orthotopic tumor cell implantation challenges, such as the bottleneck of cell engraftment. RESULTS We first conducted a genome-wide in vivo screen and identified 400 top-scoring candidate genes, which we subsequently tested again in a targeted in vivo screen to refine our drug selection process. Through this, we uncovered novel and previously unexplored druggable targets for glioblastoma. Out of these, we validated four promising target-specific drugs in preclinical glioblastoma models in downstream in vivo experiments. In addition, we investigated modes of action and resistance. CONCLUSION Our research marks a significant advancement in pursuing novel treatment strategies for glioblastoma. We have unveiled a range of synergistic combinations and paved the way for the rational design of combinatory treatment approaches to maximize the therapeutic efficacy of L19-TNF immunotherapy, laying the groundwork for future clinical translation.

A diselenide MOF-based nanomotor dual-driven by carbon monoxide and near-infrared-II light for multimodal tumor-targeted therapy

A diselenide MOF-based nanomotor dual-driven by carbon monoxide and near-infrared-II light for multimodal tumor-targeted therapy

Design and computational analysis of a novel Azurin-BR2 chimeric protein against breast cancer.

Cancer is one of most lethal diseases worldwide. Chemotherapeutics and surgeries are among the treatment facilities available for curing cancer. However due to their negative impact on normal cells and drug resistance development, new treatment strategies have yet to be developed. Some microbial products exhibit therapeutic potential for treating cancer. Pseudomonas aeruginosa Azurins have shown anticancer effects against breast cancer without affecting normal cells. To enhance its cytotoxic effect and targeted delivery, we fused Azurin with a cell-penetrating peptide (BR2) through a rigid linker and evaluated its anticancer potential via in silico analysis. The prediction of the secondary and the tertiary structures and analysis of physiochemical properties of chimeric proteins were computationally performed. The Azurin-BR2 chimeric protein has a basic nature with a molecular weight of 16.8kDa. The quality indices and validation of chimeric proteins were performed with ERRAT2 and Ramachandran plot values, respectively. The quality index of the chimeric protein was predicted to be 81% to 84.6%, and residues residing in the most favoured region were identified. The HDOCK bioinformatics tool was used for docking a chimeric protein with a cancer suppressor protein p53. The results of the current study support that an Azurin-BR2 fusion protein has a high binding affinity for p53 can induce apoptosis in cancerous cells, and can be used in tumor-targeting therapy.

The Dual Role of B Cells in the Tumor Microenvironment: Implications for Cancer Immunology and Therapy.

The tumor microenvironment (TME) is a complex and heterogeneous tissue composed of various cell types, including tumor cells, stromal cells, and immune cells, as well as non-cellular elements. Given their pivotal role in humoral immunity, B cells have emerged as promising targets for anti-tumor therapies. The dual nature of B cells, exhibiting both tumor-suppressive and tumor-promoting functions, has garnered significant attention. Understanding the distinct effects of various B cell subsets on different tumors could pave the way for novel targeted tumor therapies. This review provides a comprehensive overview of the heterogeneous B cell subsets and their multifaceted roles in tumorigenesis, as well as the therapeutic potential of targeting B cells in cancer treatment. To develop more effective cancer immunotherapies, it is essential to decipher the heterogeneity of B cells and their roles in shaping the TME.

Antitumor activities of anti‑CD44 monoclonal antibodies in mouse xenograft models of esophageal cancer.

CD44 is a type I transmembrane glycoprotein associated with poor prognosis in various solid tumors. Since CD44 plays a critical role in tumor development by regulating cell adhesion, survival, proliferation and stemness, it has been considered a target for tumor therapy. Anti‑CD44 monoclonal antibodies (mAbs) have been developed and applied to antibody‑drug conjugates and chimeric antigen receptor‑T cell therapy. Anti-pan‑CD44 mAbs, C44Mab‑5 and C44Mab‑46, which recognize both CD44 standard (CD44s) and variant isoforms were previously developed. The present study generated a mouse IgG2a version of the anti‑pan‑CD44 mAbs (5‑mG2a and C44Mab‑46‑mG2a) to evaluate the antitumor activities against CD44‑positive cells. Both 5‑mG2a and C44Mab‑46‑mG2a recognized CD44s‑overexpressed CHO‑K1 (CHO/CD44s) cells and esophageal tumor cell line (KYSE770) in flow cytometry. Furthermore, both 5‑mG2a and C44Mab‑46‑mG2a could activate effector cells in the presence of CHO/CD44s cells and exhibited complement-dependent cytotoxicity against both CHO/CD44s and KYSE770 cells. Furthermore, the administration of 5‑mG2a and C44Mab‑46‑mG2a significantly suppressed CHO/CD44s and KYSE770 xenograft tumor development compared with the control mouse IgG2a. These results indicate that 5‑mG2a and C44Mab‑46‑mG2a could exert antitumor activities against CD44‑positive cancers and be a promising therapeutic regimen for tumors.

Aberrant Energy Metabolism in Tumors and Potential Therapeutic Targets.

Energy metabolic reprogramming is frequently observed during tumor progression as tumor cells necessitate adequate energy production for rapid proliferation. Although current medical research shows promising prospects in studying the characteristics of tumor energy metabolism and developing anti-tumor drugs targeting energy metabolism, there is a lack of systematic compendiums and comprehensive reviews in this field. The objective of this study is to conduct a systematic review on the characteristics of tumor cells' energy metabolism, with a specific focus on comparing abnormalities between tumor and normal cells, as well as summarizing potential targets for tumor therapy. Additionally, this review also elucidates the aberrant mechanisms underlying four major energy metabolic pathways (glucose, lipid, glutamine, and mitochondria-dependent) during carcinogenesis and tumor progression. Through the utilization of graphical representations, we have identified anomalies in crucial energy metabolism pathways, encompassing transporter proteins (glucose transporter, CD36, and ASCT2), signaling molecules (Ras, AMPK, and PTEN), as well as transcription factors (Myc, HIF-1α, CREB-1, and p53). The key molecules responsible for aberrant energy metabolism in tumors may serve as potential targets for cancer therapy. Therefore, this review provides an overview of the distinct energy-generating pathways within tumor cells, laying the groundwork for developing innovative strategies for precise cancer treatment.

Enhanced in vivo Stability and Antitumor Efficacy of PEGylated Liposomes of Paclitaxel Palmitate Prodrug.

The clinical use of paclitaxel (PTX) in cancer treatment is limited by its poor water solubility, significant toxicity, and adverse effects. This study aimed to propose a straightforward and efficient approach to enhance PTX loading and stability, thereby offering insights for targeted therapy against tumors. We synthesized a paclitaxel palmitate (PTX-PA) prodrug by conjugating palmitic acid (PA) to PTX and encapsulating it into liposomal vehicles using a nano delivery system. Subsequently, we investigated the in vitro and in vivo performance as well as the underlying mechanisms of PTX-PA liposomes (PTX-PA-L). PTX had a remarkable antitumor effect in vivo and significantly decreased the myelosuppressive toxicity of PTX. Moreover, the introduction of PA increased the lipid solubility of PTX, forming a phospholipid bilayer as a membrane stabilizer, prolonging the circulation time of the drug and indirectly increasing the accumulation of liposomes at the tumor site. Our in vivo imaging experiments demonstrated that PTX-PA-L labeled with DiR has greater stability in vivo than blank liposomes and that PTX-PA-L can target drugs to the tumor site and efficiently release PTX to exert antitumor effects. In a mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was approximately twofold greater than that of Taxol. However, in a nude mouse model, the concentration of PTX at the tumor site in the PTX-PA-L group was only approximately 0.8-fold greater than that of Taxol. Furthermore, the originally observed favorable pharmacodynamics in normal mice were reversed following immunosuppression. This may be caused by differences in esterase distribution and immunity. This prodrug technology combined with liposomes is a simple and effective therapeutic strategy with promising developmental prospects in tumor-targeted therapy owing to its ability to convert PTX into a long-circulating nano drug with low toxicity, high pharmacodynamics, and good stability in vivo.

Collagen-disruptive cell therapy: adoptive transfer of membrane-anchored, tumor cell surface vimentin-targeted interleukin 12-armed TILs suppress collagen expression to boost deep T-cell infiltration via dual signaling activation and significant CCKAR reduction.

Tumor-targeted T-cell therapies of various types have been booming, but T-cell therapy is limited by its inability to penetrate the collagen barrier surrounding tumors. The destruction of tumor collagen is significant because collagen both suppresses T cells and contributes to the formation of the extracellular matrix. Our previously reported cell surface vimentin (CSV)-targeted and membrane-anchored IL12-armed (attIL12) T cells can reduce collagen production by killing cancer-associated fibroblasts, thereby increasing T-cell infiltration. However, attIL12-T cells cannot reduce collagen expression by tumors that highly express CCKAR. In this study, we discovered that CCKAR directly boosts collagen production by tumor cells in vitro and in vivo. attIL12-modified tumor-infiltrating lymphocytes (TILs) disabled collagen production by CCKAR-high autologous tumor cells in vitro and sarcoma patient-derived xenografts (PDXs) in vivo. This disruption of collagen production by tumor cells required a simultaneous interaction between the CSV on autologous tumor cells, which is targeted by attIL12, and HLA-TCR on attIL12-TILs; when either interaction was abrogated, collagen production and CCKAR expression were not shut down. Mechanistically, the interaction between attIL12-TILs and autologous tumor cells synergized IFNγ production, which in combination with CCKAR downregulation reduced collagen expression through suppression of both TGFβ-stimulated SMAD activation and CCKAR-AKT signaling. Diminishing collagen expression from tumor cells significantly increased T-cell infiltration and improved tumor growth inhibition in PDX sarcomas. This study thus uncovers the first tumor collagen-disrupting T-cell therapy we know of. This is significant because collagen is enriched in most high-grade CCKAR+ human sarcomas. Thus, this attIL12-TIL therapy holds great clinical potential for boosting T-cell infiltration in high-grade, collagen-rich tumors.

Role of four and a half LIM domain protein 1 in tumors (Review).

As a cytoskeletal protein, the four and a half LIM domain protein 1 (FHL1) is widely expressed in various cells, particularly skeletal and cardiac muscle cells. FHL1 is involved in the development of the skeletal muscle and myocardium, regulations of gene transcription and thyroid function, and other physiological processes. Its expression is closely related to numerous diseases, such as skeletal muscle disease and viral infections. With the advances in research, the role of FHL1 in the development of tumors is also being revealed. The mechanism of FHL1 in the regulation of tumor growth is complex and is becoming a research focus. It is also expected to become a potential target for tumor therapy. Therefore, the present article reviewed the progress in research on the role of FHL1 in cancer.