Tumor Site Research Articles

Nanoplatforms derived from iron dextran combined with ascorbic acid for enhanced photothermal-chemodynamic therapy of tumors

The current limitations of chemodynamic therapy (CDT) are mainly due to the lack of metal ions (Fe2+, Cu+, etc.), glutathione overexpression, and insufficient hydrogen peroxide level in the tumor microenvironment. Here, we constructed a safe and effective nanoplatform (abbreviate as MPCF, M: 4T1 cell membranes; P: polydopamine; C: calcium phosphate; F: iron dextran) for tumor CDT applications based on ascorbic acid and iron dextran, which is clinically used in the treatment of iron deficiency anemia. The MPCF was fabricated by encapsulating iron dextran nanoparticles within porous calcium phosphate nanoparticle carriers and surface modifying with polydopamine and 4T1 tumor cell membranes. The MPCF can efficiently accumulate at tumor sites and gradually degrade to release the encapsulated iron dextran nanoparticles in response to the acidic tumor microenvironment. Intraperitoneally injected ascorbic acid not only generated hydrogen peroxide at the tumor site, but also synergistically acted with endogenous glutathione to reduce trivalent iron ions in the iron dextran to divalent iron ions, leading to depletion of the excess glutathione at the tumor site and amplification of oxidative stress effects. In addition, polydopamine-mediated photothermal therapy (PTT) can further enhance the CDT effect. In vitro and in vivo experiments demonstrated that the combination therapy of CDT and PTT based on the MPCF exhibited effective tumor inhibition and good biosafety properties. Therefore, the nanoplatforms prepared with the clinical drug iron dextran provide a new idea for the design of nanoprobes of tumor therapy with clinical translational potential.

Epidemiological trends of synovial sarcoma by primary tumor sites in the US from 2000 to 2020

BackgroundSynovial sarcoma (SS) is a rare soft-tissue cancer. Existing literature encompasses Surveillance, Epidemiology, and End Results (SEER) data-based research on SS explaining the incidence-prevalence in general, by subtypes, and by age at diagnosis. Therefore, this study aimed to fill in the gap of knowledge about measures of disease occurrence and burden of SS by tumor site using the SEER database. MethodsIn this cross-sectional study, primary SS patients were selected from SEER 17 Registries, Nov. 2021 (2000–2020) using ICD-O-3 codes 9040, 9041, 9042, and 9043. Patients with additional cancers were excluded. The primary tumor site was categorized into (1) head/neck, (2) internal thorax, (3) abdomen/pelvis, (4) upper extremity, and (5) lower extremity using ICD-10CM codes. Five outcomes were analyzed: age-adjusted incidence rate, 5-year limited-duration prevalence rate, incidence-based mortality, case-fatality rate, and overall survival. ResultsFrom 2000–2020, the overall age-adjusted incidence rate was 0.15 per 100,000; the 5-year limited duration prevalence rate was 0.56 per 100,000; and the incidence-based mortality rate was 0.06 per 100,000 people. The case-fatality and 5-year OS rates were 39.2 % and 62.9 %, respectively. Lower extremity had the highest incidence of 0.07 (estimated 1166 cases), prevalence of 0.36 (estimated 224 cases), and mortality rate of 0.025 (estimated 429 deaths) per 100,000. The other four locations had much closer rates with each other. Intrathoracic SS had the highest case-fatality rate of 71.5 % (148/207) and lowest 5-year OS of 26.0 % (95 % CI: 19.6 %, 32.9 %) than other sites. ConclusionBased on the measures of disease frequency, the most common primary tumor site is the lower extremity, followed by the upper extremity, abdomen/pelvis, internal thorax, and head/neck. The least favorable primary location is the internal thorax. Those with a primary location of the upper extremity have the longest overall survival, followed by the head/neck, lower extremity, abdomen/pelvis, and internal thorax.

Gold Nanocluster: A Photoelectric Converter for X-Ray-Activated Chemotherapy.

Despite the promise of activatable chemotherapy, the development of a spatiotemporally controllable strategy for prodrug activation in deep tissues remains challenging. Herein, a proof-of-concept is proposed for a gold nanocluster-based strategy that utilizes X-ray irradiation to trigger the liberation of platinum (Pt)-based prodrug conjugates, thus enabling radiotherapy-directed chemotherapy. Mechanistically, the irradiated activation of prodrugs is achieved through direct photoelectron transfer from the excited-state gold nanoclusters to the Pt(IV) center, resulting in the release of cytotoxic Pt(II) agents. Compared to the traditional combination of chemotherapy and radiotherapy, this radiotherapy-directed chemotherapy strategy offers superior antitumor efficacy and safety benefits through spatiotemporal synergy at the tumor site. Additionally, this strategy elicits robust immunogenic cell death and yields profound outcomes for combined immunotherapy of breast cancer. This versatile strategy is ushering in a new era of radiation-mediated chemistry for controlled drug delivery and the precise regulation of biological processes.

18F-FDG PET/CT for early prediction of pathological complete response in breast cancer neoadjuvant therapy: a retrospective analysis.

Neoadjuvant treatment has been developed as a systematic approach for patients with early breast cancer and has resulted in improved breast-conserving rate and survival. However, identifying treatment-sensitive patients at the early phase of therapy remains a problem, hampering disease management and raising the possibility of disease progression during treatment. In this retrospective analysis, we collected 2-deoxy-2-[F-18] fluoro-d-glucose (18F-FDG) positron emission tomography (PET)/computed tomography (CT) images of primary tumor sites and axillary areas and reciprocal clinical pathological data from 121 patients who underwent neoadjuvant treatment and surgery in our center. The univariate and multivariate logistic regression analyses were performed to investigate features associated with pathological complete response (pCR). An 18F-FDG PET/CT-based prediction model was trained, and the performance was evaluated by receiver operating characteristic curves (ROC). The maximum standard uptake values (SUVmax) of 18F-FDG PET/CT were a powerful indicator of tumor status. The SUVmax values of axillary areas were closely related to metastatic lymph node counts (R = 0.62). Moreover, the early SUVmax reduction rates (between baseline and second cycle of neoadjuvant treatment) were statistically different between pCR and non-pCR patients. The early SUVmax reduction rates-based model showed great ability to predict pCR (AUC = 0.89), with all molecular subtypes (HR+HER2-, HR+HER2+, HR-HER2+, and HR-HER2-) considered. Our research proved that the SUVmax reduction rate of 18F-FDG PET/CT contributed to the early prediction of pCR, providing rationales for utilizing PET/CT in NAT in the future.

Illuminating immunotherapy response via precision T cell-targeted PET imaging

Traditionally, immunotherapy agent selection and treatment strategies are guided by biopsy-based histological information. However, biopsies are limited in that they are invasive, provide static information regarding the tumor immune microenvironment, and only sample a small part of one tumor site. The tumor microenvironment is dynamic and heterogenous. As a result, the immune milieu at one site may be distinct from other metastatic sites. These factors make identifying which patients are likely to respond to different immunotherapies and which harbor intrinsic resistance mechanisms difficult to identify based on a biopsy alone. As such, there is significant interest in alternative methodologies that better characterize the tumor immune microenvironment and monitor immunotherapy response. PET imaging potentially offers a non-invasive way to characterize the tumor immune microenvironment at the primary tumor and metastases and allow for longitudinal characterization. Herein, we review pre-clinically and clinically tested T cell-targeted PET radiopharmaceuticals, as T cells have been the dominant immunotherapy target, and their utility in both evaluating response to immunotherapy and in understanding the systemic immune response to treatment with immunotherapeutics.

Unravelling the role of tumor microenvironment responsive nanobiomaterials in spatiotemporal controlled drug delivery for lung cancer therapy.

Design and development of efficient drug delivery technologies that impart site-specificity is the need of the hour for the effective treatment of lung cancer. The emergence of materials science and nanotechnology partially helped drug delivery scientists to achieve this objective. Various stimuli-responsive materials that undergo degradation at the pathological tumor microenvironment (TME) have been developed and explored for drug delivery applications using nanotechnological approaches. Nanoparticles (NPs), owing to their small size and high surface area to volume ratio, demonstrated enhanced cellular internalization, permeation, and retention at the tumor site. Such passive accumulation of stimuli-responsive materials helped to achieve spatiotemporally controlled and targeted drug delivery within the tumors. In this review, we discussed various stimuli-physical (interstitial pressure, temperature, and stiffness), chemical (pH, hypoxia, oxidative stress, and redox state), and biological (receptor expression, efflux transporters, immune cells, and their receptors or ligands)-that are characteristic to the TME. We mentioned an array of biomaterials-based nanoparticulate delivery systems that respond to these stimuli and control drug release at the TME. Further, we discussed nanoparticle-based combinatorial drug delivery strategies. Finally, we presented our perspectives on challenges related to scale-up, clinical translation, and regulatory approvals.

Carrier-Free Photodynamic Bioregulators Inhibiting Lactic Acid Efflux Combined with Immune Checkpoint Blockade for Triple-Negative Breast Cancer Immunotherapy.

Abnormal tumor metabolism creates a complex tumor immune microenvironment that plays a dominant role in the metastasis of triple-negative breast cancer (TNBC). TNBC is insensitive to immune checkpoint blockade (ICB) therapy because of insufficient cytotoxic T lymphocyte (CTL) infiltration and a hyper-lactic acid-suppressive immune microenvironment caused by abnormal glycolysis. Herein, we propose an amplified strategy based on lactic acid regulation to reprogram the immunosuppressive tumor microenvironment (ITM) and combine it with ICB therapy to achieve enhanced antitumor immunotherapy effects. Specifically, we constructed CASN, a carrier-free photodynamic bioregulator, through the self-assembly of the photosensitizer Chlorin e6 and monocarboxylate transporter 1 (MCT1) inhibitor AZD3965. CASN exhibited a uniform structure, good stability, and drug accumulation at the tumor site. CASN-mediated photodynamic therapy following laser irradiation inhibited primary tumor growth and induced immunogenic cell death. Furthermore, CASN reduced lactic acid-mediated regulatory T cell generation and M2 tumor-associated macrophage polarization by blocking MCT1-mediated lactic acid efflux to attenuate immune suppression, inducing the recruitment and activation of CTLs. Ultimately, CASN-mediated immunopotentiation combined with ICB therapy considerably strengthened tumor immunotherapy and effectively inhibited tumor growth and metastasis of TNBC. This synergistic amplification strategy overcomes the limitations of an acidic ITM and presents a potential clinical treatment option for metastatic tumors.

FeAu Bimetallic Nanoparticle as Fe(0) Reservoir for Near Infrared Laser Enhanced Ferroptosis/Pyroptosis‐Based Tumor Immunotherapy

AbstractIron (Fe)‐based nanoparticles (NPs) have attracted considerable attention in nanomedicine research due to their enhancement effects in magnetic resonance imaging (MRI) and cancer therapy. Although zero‐valent Fe (Fe(0)) can serve as an active catalyst to decompose H2O2 into reactive oxygen species (ROS), its activity is compromised in physiological conditions due to its susceptibility to oxidation. Here it is reported that a 9 nm FeAu alloy NP system can efficiently stabilize Fe(0) in neutral pH solution, but release Fe(0) in tumor‐bearing environment, catalyzing H2O2 decomposition to ROS. Although Fe3O4 NPs and Au NPs are well‐known for their biocompatible, FeAu NPs effectively eliminate cancer cells at an IC50 as low as 15 µg mL−1 Fe. Further proteomics analysis reveals that FeAu NPs can concomitantly induce both ferroptosis and pyroptosis. Additional near‐infrared (NIR) irradiation further increases cell death and promotes maturation of dendritic cells within tumor‐draining lymph nodes and infiltration of helper T cells and cytotoxic T lymphocytes within tumor sites, resulting in significant reduction in tumor growth and metastasis. The studies demonstrate a great potential of FeAu NPs as a stable Fe(0) reservoir for pH/NIR controlled Fe(0) release and further for ferroptosis and pyroptosis co‐mediated tumor immunotherapy.

Determining M2 macrophages content for the anti-tumor effects of metal-organic framework-encapsulated pazopanib nanoparticles in breast cancer

Pazopanib (PAZ), an oral multi-tyrosine kinase inhibitor, demonstrates promising cytostatic activities against various human cancers. However, its clinical utility is limited by substantial side effects and therapeutic resistance. We developed a nanoplatform capable of delivering PAZ for enhanced anti-breast cancer therapy. Nanometer-sized PAZ@Fe-MOF, compared to free PAZ, demonstrated increased anti-tumor therapeutic activities in both syngeneic murine 4T1 and xenograft human MDA-MB-231 breast cancer models. High-throughput single-cell RNA sequencing (scRNAseq) revealed that PAZ@Fe-MOF significantly reduced pro-tumorigenic M2-like macrophage populations at tumor sites and suppressed M2-type signaling pathways, such as ATF6-TGFBR1-SMAD3, as well as chemokines including CCL17, CCL22, and CCL24. PAZ@Fe-MOF reprogramed the inhibitory immune microenvironment and curbed tumorigenicity by blocking the polarization of M2 phenotype macrophages. This platform offers a promising and new strategy for improving the cytotoxicity of PAZ against breast cancers. It provides a method to evaluate the immunological response of tumor cells to PAZ-mediated treatment.

Supramolecular self-sensitized dual-drug nanoassemblies potentiating chemo-photodynamic therapy for effective cancer treatment

Chemo-photodynamic synergistic therapy (CPST) holds tremendous promise for treating cancers. Unfortunately, existing CPST applications suffer from complex synthetic procedures, low drug co-loading efficiency, and carrier-related toxicity. To address these issues, we have developed a supramolecular carrier-free self-sensitized nanoassemblies by co-assembling podophyllotoxin (PTOX) and chlorin e6 (Ce6) to enhance CPST efficiency against tumors. The nanoassemblies show stable co-assembly performance in simulative vivo neural environment (∼150 nm), with high co-loading ability for PTOX (72.2 wt%) and Ce6 (27.8 wt%). In vivo, the nanoassemblies demonstrate a remarkable ability to accumulate at tumor sites by leveraging the enhanced permeability and retention (EPR) effect. The disintegration of nanoassemblies following photosensitizer bioactivation triggered by the acidic tumor environment effectively resolves the challenge of aggregation-caused quenching (ACQ) effect. Upon exposure to external light stimulation, the disintegrated nanoassemblies not only illuminate cancer cells synergistically but also exert a more potent antitumor effect when compared with PTOX and Ce6 administered alone. This self-sensitized strategy represents a significant step forward in CPST, offering a unique co-delivery paradigm for clinic cancer treatment.

Nanomaterial-Mediated Delivery of MLKL Plasmids Sensitizes Tumors to Immunotherapy and Reduces Metastases.

Cancer immunotherapy has emerged as a promising approach for the induction of an antitumor response. While immunotherapy response rates are very high in some cancers, the efficacy against solid tumors remains limited caused by the presence of an immunosuppressive tumor microenvironment. Induction of immunogenic cell death (ICD) in the tumor can be used to boost immunotherapy response in solid cancers by eliciting the release of immune-stimulatory components. However, the delivery of components inducing ICD to tumor sites remains a challenge. Here, a novel delivery method is described for antitumor therapy based on MLKL (Mixed Lineage Kinase Domain-Like), a key mediator of necroptosis and inducer of ICD. A novel highly branched poly (β-amino ester)s (HPAEs) system is designed to efficiently deliver MLKL plasmid DNA to the tumor with consequent enhancement of immune antigen presentation for T cell responses in vitro, and improved antitumor response and prolonged survival in tumor-bearing mice. Combination of the therapy with anti-PD-1 treatment revealed significant changes in the composition of the tumor microenvironment, including increased infiltration of CD8+ T cells and tumor-associated lymphocytes. Overall, the HPAEs delivery system can enhance MLKL-based cancer immunotherapy and promote antitumor immune responses, providing a potential treatment to boost cancer immunotherapies.

Interference of ATP-Adenosine Axis by Engineered Biohybrid for Amplifying Immunogenic Cell Death-Mediated Antitumor Immunotherapy.

Immunogenic cell death (ICD) often results in the production and accumulation of adenosine (ADO), a byproduct that negatively impacts the therapeutic effect as well as facilitates tumor development and metastasis. Here, an innovative strategy is elaborately developed to effectively activate ICD while avoiding the generation of immunosuppressive adenosine. Specifically, ZIF-90, an ATP-responsive consumer, is synthesized as the core carrier to encapsulate AB680 (CD73 inhibitor) and then coated with an iron-polyphenol layer to prepare the ICD inducer (AZTF), which is further grafted onto prebiotic bacteria via the esterification reaction to obtain the engineered biohybrid (Bc@AZTF). Particularly, the designed Bc@AZTF can actively enrich in tumor sites and respond to the acidic tumor microenvironment to offload AZTF nanoparticles, which can consume intracellular ATP (iATP) content and simultaneously inhibit the ATP-adenosine axis to reduce the accumulation of adenosine, thereby alleviating adenosine-mediated immunosuppression and strikingly amplifying ICD effect. Importantly, the synergy of anti-PD-1 (αPD-1) with Bc@AZTF not only establishes a collaborative antitumor immune network to potentiate effective tumoricidal immunity but also activates long-lasting immune memory effects to manage tumor recurrence and rechallenge, presenting a new paradigm for ICD treatment combined with adenosine metabolism.

Emerging cancer disease burden in a rural sub-Saharan African population: northeast Nigeria in focus

IntroductionSub-Saharan Africa (SSA) is plagued by myriads of diseases, mostly infectious; but cancer disease burden is rising among non-communicable diseases. Nigeria has a high burden of cancer, however its remote underserved culturally-conserved populations have been understudied, a gap this study sought to fill.MethodsThis was a cross-sectional multi-institutional descriptive study of histologically diagnosed cancers over a four-year period (January 2019-December 2022) archived in the Departments of Pathology and Cancer Registries of six tertiary hospitals in the northeast of Nigeria. Data obtained included age at diagnosis, gender, tumor site and available cancer care infrastructure. Population data of the study region and its demographics was obtained from the National Population Commission and used to calculate incident rates for the population studied.ResultsA total of 4,681 incident cancer cases from 2,770 females and 1,911 males were identified. The median age at diagnosis for females was 45 years (range 1–95yrs), and 56 years (range 1–99yrs) for males. Observed age-specific incidence rates (ASR) increased steadily for both genders reaching peaks in the age group 80 years and above with the highest ASR seen among males (321/100,000 persons) compared to females (215.5/100,000 persons). Breast, cervical, prostatic, colorectal and skin cancers were the five most common incident cancers. In females, breast, cervical, skin, ovarian and colorectal cancers were the top five malignancies; while prostate, haematolymphoid, skin, colorectal and urinary bladder cancers predominated in men.ConclusionRemote SSA communities are witnessing rising cancer disease burden. Proactive control programs inclusive of advocacy, vaccination, screening, and improved diagnostics are needed.

Integration of photomagnetic bimodal imaging to monitor an autogenous exosome loaded platform: unveiling strong targeted retention effects for guiding the photothermal and magnetothermal therapy in a mouse prostate cancer model

BackgroundProstate cancer (PCa) is the most prevalent cancer among males, emphasizing the critical need for precise diagnosis and treatment to enhance patient prognosis. Recent studies have extensively utilized urine exosomes from patients with cancer for targeted delivery. This study aimed to employ highly sensitive magnetic particle imaging (MPI) and fluorescence molecular imaging (FMI) to monitor the targeted delivery of an exosome-loaded platform at the tumour site, offering insights into a potential combined photothermal and magnetic thermal therapy regime for PCa.ResultsMPI and FMI were utilized to monitor the in vivo retention performance of exosomes in a prostate tumour mouse model. The exosome-loaded platform exhibited robust homologous targeting ability during imaging (SPIONs@EXO-Dye:66·48%±3·85%; Dye-SPIONs: 34·57%±7·55%, **P<0·01), as verified by in vitro imaging and in vitro tissue Prussian blue staining.ConclusionsThe experimental data underscore the feasibility of using MPI for in vivo PCa imaging. Furthermore, the exosome-loaded platform may contribute to the precise diagnosis and treatment of PCa.Graphical

Deep Learning for the Accurate Prediction of Triggered Drug Delivery.

The need to mitigate the adverse effects of chemotherapy has driven the exploration of innovative drug delivery approaches. One emerging trend in cancer treatment is the utilization of Drug Delivery Systems (DDSs), facilitated by nanotechnology. Nanoparticles, ranging from 1 nm to 1000 nm, act as carriers for chemotherapeutic agents, enabling precise drug delivery. The triggered release of these agents is vital for advancing this novel drug delivery system. Our research investigated this multifaceted delivery capability using liposomes and metal organic frameworks as nanocarriers and utilizing all three targeting techniques: passive, active, and triggered. Liposomes are modified using targeting ligands to render them more targeted toward certain cancers. Moieties are conjugated to the surfaces of these nanocarriers to allow for their binding to receptors overexpressed on cancer cells, thus increasing the accumulation of the agent at the tumor site. A novel class of nanocarriers, namely metal organic frameworks, has emerged, showing promise in cancer treatment. Triggering techniques (both intrinsic and extrinsic) can be used to release therapeutic agents from nanoparticles, thus enhancing the efficacy of drug delivery. In this study, we develop a predictive model combining experimental measurements with deep learning techniques. The model accurately predicts drug release from liposomes and MOFs under various conditions, including low- and high-frequency ultrasound (extrinsic triggering), microwave exposure (extrinsic triggering), ultraviolet light exposure (extrinsic triggering), and different pH levels (intrinsic triggering). The deep learning-based predictions significantly outperform linear predictions, proving the utility of advanced computational methods in drug delivery. Our findings demonstrate the potential of these nanocarriers and highlight the efficacy of deep learning models in predicting drug release behavior, paving the way for enhanced cancer treatment strategies.

"GLI1 Subcellular Localization and Overexpression as Prognostic Factors for Disease-Free Survival in Colorectal Carcinoma".

Glioma-associated oncogene homolog-1 (GLI1) is amplified in human glioblastoma, and there is growing evidence suggesting its significant role in tumor development and metastasis. Our aim was to investigate the role of the GLI-1 gene in the progression of colorectal cancer (CRC) and its correlation with various clinicopathological features. Additionally, we examined the impact of the GLI-1 gene and other factors on the prognosis of CRC. We analyzed a total of 98 confirmed CRC cases and adjacent normal tissue controls. Patients suspected of having colon cancer underwent a colonoscopy and targeted biopsy, while those with rectal cancer underwent CT scans and MRI. GLI1 expression was detected using real-time PCR assay, Western blotting, and immunohistochemistry. The GLI1 gene was observed to be overexpressed in tumor tissues at both the protein and mRNA levels (p < 0.05). In addition, GLI1 overexpression was significantly associated with various factors such as tumor invasion (T3/T4), presence of lymph nodes, lymph node metastasis (LNM), stage (III/IV), tumor site (colon), tumor size (≥ 3cm), localization (nucleocytoplasmic), strong staining intensity and recurrence (p < 0.05). The results of survival analysis showed that the patients with overexpression of GLI1 had a significantly lower DFS rate which was 21months compared to those with normal expression who had 31months (p < 0.05). Moreover, individuals with early onset disease (15months) were more likely to have cytoplasmic localization of the GLI1 gene as opposed to nucleo-cytoplasmic localization of GLI1 which presented late-onset disease( 23months) (p < 0.05). Finally, Stage and PNI (p < 0.05) were found to independently affect outcomes of CRC according to Cox regression analysis. High expression of GLI-1 in CRC is associated with adverse pathology and poor prognosis for patients. The correlation between cytoplasmic localization of GLI-1 and reduced disease-free survival holds potential for guiding prognosis and treatment. Further research is needed to develop strategies targeting GLI-1 for improved outcomes.

Dual‐Targeted Engineered Bacterial Outer Membrane Vesicles for Hepatocellular Carcinoma Immunotherapy

AbstractCluster of differentiation 47 (CD47) is an important innate immune checkpoint that empowers tumors to send “don't eat me” signals, leading to immune escape. CD47 monoclonal antibodies have achieved remarkable therapeutic success in hematological malignancies. However, their efficacy in solid tumors is limited, mainly because of immunosuppression in the tumor microenvironment. In addition, hematotoxicity severely hinders the clinical translation of CD47 antibodies. Here, a novel genetically programmed nanovesicle, OMV‐CD47/GPC3, is generated for hepatocellular carcinoma (HCC) immunotherapy by fusing anti‐CD47 nanobodies and anti‐GPC3 scFv onto bacterial outer membrane vesicles (OMVs). Following intravenous administration, dual‐targeted OMV‐CD47/GPC3 specifically recognized tumor cells expressing both CD47 and GPC3, thereby actively targeting and accumulating at the orthotopic HCC tumor site without hematotoxicity. OMV‐CD47/GPC3 potently blocked tumor CD47 and promoted macrophage phagocytosis. More importantly, immunogenic OMV‐CD47/GPC3 can effectively remodel the tumor immune microenvironment of orthotopic HCC, especially reprogram tumor‐associated macrophages (TAMs) to the M1‐phenotype and promote dendritic cell maturation, synergistically inducing a robust CD8+ T cell‐mediated anti‐tumor immune response. With the two‐pronged approach of immune checkpoint inhibition and immune activation, engineered OMV‐CD47/GPC3 significantly suppressed orthotopic HCC growth and prevented tumor recurrence and metastasis, thus providing a promising strategy for HCC immunotherapy.

Potentiating light-harvesting tactics through an A-D-A structure: repolarization of tumor-associated macrophages through phototherapy.

Aiming to decrease the recurrence of tumors and achieve patient satisfaction, the elicitation of immunotherapy and its integrated synergistic employment is a bright new direction in oncotherapy, yet an emergently challenging task. In particular, tumor-associated macrophage (TAM) regulation though light-induced photodynamic and photothermal therapy (PDT and PTT) is regarded as a powerful approach, which focuses on the systemic immune system instead of the tumor itself. Herein, this study reports an acceptor-donor-acceptor (A-D-A) aggregation-induced emission luminogen (AIEgen), named TPA-2CN, which was applied as a photosensitizer (PS) and photothermal agent (PTA). Attributed to its A-D-A structure and AIE properties, TPA-2CN exhibits a high molar absorption coefficient and acts as a perfect template in regulating radiative and nonradiative transitions, which mainly utilize excited energy. The generation of type I reactive oxygen promoted its application in hypoxic tumor sites and the combination of hyperpyrexia forcefully induces macrophages to polarize towards the immune response M1 phenotype. In in vitro and in vivo, the successful reversion and reprogramming of the immune microenvironment was impressively proved. This method optimally concentrated immune therapy, PDT and PTT as one and exhibited excellent synergistic therapeutic effects with good biosafety.

Surgical Interventions Following Radiotherapy in Spinal Metastases with Intermediate Instability: A Risk Factor Analysis: The Korean Society of Spinal Tumor Multicenter Study (KSST 2022-02)

Background: One important determinant in choosing a treatment modality is spinal instability. Clear management guidelines are suggested for stable and unstable spinal metastatic lesions, but lesions in the intermediate instability category (SINS [spinal instability neoplastic score] score of 7–12) remain a clinical dilemma. This study aims to analyze the risk factors necessitating surgical intervention after radiotherapy (RT) in patients with those lesions. Methods: A multicenter cohort of 469 patients with spinal metastases of intermediate instability who received radiotherapy (RT) as the initial treatment between 2019 and 2021 were retrospectively enrolled. All patients were neurologically intact at the time of RT. According to the performance of surgical intervention after RT, various clinical and radiographic risk factors for surgical intervention were compared between surgery and non-surgery groups using uni- and multivariate analyses. A recursive partitioning analysis (RPA) was performed using significant determinants identified in multivariate analysis. Results: The mean age at the time of RT was 59.9 years and there were 198 females. The lung was the most common primary site. During the mean follow-up duration of 18.2 months, surgical treatment was required in 79 (17.9%) of patients. The most common surgical method was decompressive laminectomy with stabilization (62.0%), followed by vertebrectomy with stabilization (22.8%) and stabilization only (15.2%). The mean SINS for the total cohort was 9.0. Multivariate regression analyses revealed that the primary tumor site of the lung, liver, and kidney, higher Bilsky grades of ESCC, lytic bone lesions, and higher EQD210 were significant risk factors for surgical intervention after RT. Among them, Bilsky grade, primary tumor type of the lung, liver, and kidney, and EQD210 were the most important determinants for expecting the probability of surgical intervention on RPA. Conclusions: Surgical intervention was performed in 17.9% of patients with intermediate instability after RT as the initial treatment. The primary tumor site of the lung, liver, and kidney, higher Bilsky grade of ESCC, and EQD210 were the most important determinants for expecting the probability of surgical intervention. Therefore, the optimal treatment strategy needs to be devised by carefully evaluating the risk of surgical intervention.

Antibody targeting of anaerobic bacteria warms cold tumors and improves the abscopal effect of radiotherapy

BackgroundThe combination of immune checkpoint inhibitors with radiotherapy can enhance the immunomodulation by RT and reduce the growth of distant unirradiated tumors (abscopal effect); however, the results are still not very satisfactory. Therefore, new treatment options are needed to enhance this effect. Our previous study showed that the combination of Bifidobacterium (Bi) and its specific monoclonal antibody (mAb) could target and alleviate hypoxia at the tumor site and act as a radiosensitizer. In this study, we explored the anti-tumor efficacy of quadruple therapy (Bi + mAb and RT + αPD-1). The current study also aimed to probe into the complex immune mechanisms underlying this phenomenon.MethodsConstructed 4T1 breast and CT26 colon cancer tumor models. A comprehensive picture of the impact of constructed quadruple therapy was provided by tumor volume measurements, survival analysis, PET/CT imaging, immune cell infiltration analysis and cytokine expression levels.ResultsThe abscopal effect was further amplified in the “cold” tumor model and prolonged survival in tumor-bearing mice. Bi can colonized in primary and secondary tumors and direct the mAb to reach the tumor site, activate complement, enhance the ADCC effect and initiate the innate immune response. Then combined with αPD-1 and radiotherapy to stimulate adaptive immune response and synergize with cytokines to expand the immune efficacy and generate effective anti-tumor immune response.ConclusionsBi was used as an artificially implanted anaerobic target to cause a transient “infection” at the tumor, causing the tumor to become locally inflamed and “hot”, and at the same time, mAb was used to target Bi to enhance the local immune effect of the tumor, and then combined with radiotherapy and αPD-1 to amplify the abscopal effect in multiple dimensions. Therefore, the present study provided a new idea for the multipotent immune-activating function of antibody-targeted anaerobic bacteria for the RT treatment of extensively metastasized cancer patients.