Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer's disease.

Microglial involvement in Alzheimer's disease (AD) pathology has emerged as a risk-determining pathogenic event. While apolipoprotein E (APOE) is known to modify AD risk, it remains unclear how microglial apoE impacts brain cognition and AD pathology. Here, using conditional mouse models expressing apoE isoforms in microglia and central nervous system-associated macrophages (CAMs), we demonstrate a cell-autonomous effect of apoE3-mediated microglial activation and function, which are negated by apoE4. Expression of apoE3 in microglia/CAMs improves cognitive function, increases microglia surrounding amyloid plaque and reduces amyloid pathology and associated toxicity, whereas apoE4 expression either compromises or has no effects on these outcomes by impairing lipid metabolism. Single-cell transcriptomic profiling reveals increased antigen presentation and interferon pathways upon apoE3 expression. In contrast, apoE4 expression downregulates complement and lysosomal pathways, and promotes stress-related responses. Moreover, in the presence of mouse endogenous apoE, microglial apoE4 exacerbates amyloid pathology. Finally, we observed a reduction in Lgals3-positive responsive microglia surrounding amyloid plaque and an increased accumulation of lipid droplets in APOE4 human brains and induced pluripotent stem cell-derived microglia. Our findings establish critical isoform-dependent effects of microglia/CAM-expressed apoE in brain function and the development of amyloid pathology, providing new insight into how apoE4 vastly increases AD risk.

Dual-Loaded Liposomes Tagged with Hyaluronic Acid Have Synergistic Effects in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is the most lethal subtypes of breast cancer. Although chemotherapy is considered the most effective strategy for TNBC, most chemotherapeutics in current use are cytotoxic, meaning they target antiproliferative activity but do not inhibit tumor cell metastasis. Here, a TNBC-specific targeted liposomal formulation of epalrestat (EPS) and doxorubicin (DOX) with synergistic effects on both tumor cell proliferation and metastasis is described. These liposomes are biocompatible and effectively target tumor cells owing to hyaluronic acid (HA) modification on their surface. This active targeting, mediated by CD44-HA interaction, allows DOX and EPS to be delivered simultaneously to tumor cells in vivo, where they suppress not only TNBC tumor growth and the epithelial-mesenchymal transition, but also cancer stem cells, which collectively suppress tumor growth and metastasis of TNBC and may also act to prevent relapse of TNBC.

The role of radiation therapy in treatment of adults with newly diagnosed glioblastoma multiforme: a systematic review and evidence-based clinical practice guideline update.

TARGET POPULATION: These recommendations apply to adult patients diagnosed with newly diagnosed glioblastoma. QUESTION 1 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the addition of radiation therapy (RT) more beneficial than management without RT in improving survival? RECOMMENDATIONS: Level I: Radiation therapy (RT) is recommended for the treatment of newly diagnosed malignant glioblastoma in adults. QUESTION 2 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is the RT regimen of 60 Gy given in 2 Gy daily fractions more beneficial than alternative regimens in providing survival benefit while minimizing toxicity? RECOMMENDATIONS: Level I: Treatment schemes should include dosage of up to 60 Gy given in 2 Gy daily fractions that includes the enhancing area. QUESTION 3 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, is a tailored target volume superior to regional RT for reduction of radiation-induced toxicity while maintaining efficacy? RECOMMENDATION: Level II: It is recommended that radiation therapy planning include 1-2 cm margin around the radiographically T1 weighted contrast-enhancing tumor volume or the T2 weighted abnormality on MRI. Level III: Recalculation of the radiation volume during RT treatment may be necessary to reduce the radiated volume of normal brain since the volume of surgical defect will change during the long period of RT. QUESTION 4 : In adult patients (aged 65 and under) with newly diagnosed glioblastoma, does the addition of RT of the subventricular zone to standard tumor volume treatment improve tumor control and overall survival? RECOMMENDATION: No recommendation can be formulated as there is contradictory evidence in favor of and against intentional radiation of the subventricular zone (SVZ) QUESTION 5 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does the addition of RT to surgical intervention improve disease control and overall survival? RECOMMENDATION: Level I: Radiation therapy is recommended for treatment of elderly and frail patients with newly diagnosed glioblastoma to improve overall survival. QUESTION 6 : In elderly (age > 65 years) and/or frail patients with newly diagnosed glioblastoma, does modification of RT dose and fractionation scheme from standard regimens decrease toxicity and improve disease control and survival? RECOMMENDATION: Level II: Short RT treatment schemes are recommended in frail and elderly patients as compared to conventional 60 Gy given in 2 daily fractions because overall survival is not different while RT risk profile is better for the short RT scheme. Level II: The 40.05 Gy dose given in 15 fractions or 25 Gy dose given in 5 fractions or 34 Gy dose given in 10 fractions should be considered as appropriate doses for Short RT treatments in elderly and/or frail patients. QUESTION 7 : In adult patients with newly diagnosed glioblastoma is there advantage to delaying the initiation of RT instead of starting it 2 weeks after surgical intervention in decreasing radiation-induced toxicity and improving disease control and survival? RECOMMENDATION: Level III: It is suggested that RT for patients with newly diagnosed GBM starts within 6 weeks of surgical intervention as compared to later times. There is insufficient evidence to recommend the optimal specific post-operative day within the 6 weeks interval to start RT for adult patients with newly diagnosed glioblastoma that have undergone surgical resection. QUESTION 8 : In adult patients with newly diagnosed supratentorial glioblastoma is Image-Modulated RT (IMRT) or similar techniques as effective as standard regional RT in providing tumor control and improve survival? RECOMMENDATION: Level III: There is no evidence that IMRT is a better RT delivering modality when compared to conventional RT in improving overall survival in adult patients with newly diagnosed glioblastoma. Hence, IMRT should not be preferred over the Conventional RT delivery modality. QUESTION 9 : In adult patients with newly diagnosed glioblastoma does the use of radiosensitizers with RT improve the efficacy of RT as determined by disease control and overall survival? RECOMMENDATION: Level III: Iododeoxyuridine is not recommended to be used as radiosensitizer during RT treatment for patients with newly diagnosed GBM QUESTION 10 : In adult patients with newly diagnosed glioblastoma is the use of Ultrafractionated RT superior to standard fractionation regimens in improving disease control and survival? RECOMMENDATION: There is insufficient evidence to formulate a recommendation regarding the use of ultrafractionated RT schemes and patient population that could benefit from it. QUESTION 11 : In patients with poor prognosis with newly diagnosed glioblastoma is hypofractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? RECOMMENDATION: Level I: Hypofractionated RT schemes may be used for patients with poor prognosis and limited survival without compromising response. There is insufficient evidence in the literature for us to be able to recommend the optimal hypofractionated RT scheme that will confer longest overall survival and/or confer the same overall survival with less toxicities and shorter treatment time. QUESTION 12 : In adult patients with newly diagnosed glioblastoma is the addition of brachytherapy to standard fractionated RT indicated to improve disease control and survival? RECOMMENDATION: Level I: Brachytherapy as a boost to external beam RT has not been shown to be beneficial and is not recommended in the routine management of patients with newly diagnosed GBM. QUESTION 13 : In elderly patients (> 65 year old) with newly diagnosed glioblastoma under what circumstances is accelerated hyperfractionated RT indicated instead of a standard fractionation regimen as measured by extent of toxicity, disease control and survival? RECOMMENDATION: Level III: Accelerated Hyperfractionated RT with a total RT dose of 45 Gy or 48 Gy has been shown to shorten the treatment time without detriment in survival when compared to conventional external beam RT and should be considered as an option for treatment of elderly patients with newly diagnosed GBM. QUESTION 14 : In adult patients with newly diagnosed glioblastoma is the addition of Stereotactic Radiosurgery (SRS) boost to conventional standard fractionated RT indicated to improve disease control and survival? RECOMMENDATION: Level I: Stereotactic Radiosurgery boost to external beam RT has not been shown to be beneficial and is not recommended in patients undergoing routine management of newly diagnosed malignant glioma.

Visualization of Hepatocellular Regeneration in Mice After Partial Hepatectomy.

BACKGROUND: Although hepatocellular regeneration is the cornerstone of liver homeostasis, current techniques for assessing such regeneration are limited. A method for visualizing the regeneration process would provide a means for advanced studies. Therefore, we examined the possibility of using fluorescence ubiquination-based cell cycle indicator (Fucci) mice for direct visualization of hepatocellular regeneration. MATERIALS AND METHODS: We performed a two-thirds partial hepatectomy in conventional and Fucci mice. Fucci animals have orange Cdt1 expressed in the G1 phase and green Geminin expressed in S/G2/M phases. Regenerating livers were procured daily for 7 d. Immunohistochemical staining was performed for proliferative Ki67 and mitotic pHH3 serine 10 (pHH3) markers on formalin-fixed, paraffin-embedded tissue sections from conventional mice. The orange Cdt1 and green Geminin fluorescence indicative of the G1 and S/G2/M phases, respectively, were assessed in liver tissues, in vivo and ex vivo, with two-photon laser scanning microscopy. RESULTS: Immunostaining with Ki67 and pHH3 revealed a typical profile of hepatocellular regeneration after hepatectomy in conventional mice, although immunostaining required more than a week to process. In contrast, hepatocellular regeneration could be visualized with two-photon microscopy within a few hours in regenerating livers of the Fucci mice. Only orange G1 hepatocytes were seen in the baseline liver specimens; however, multiple bright green and yellow hepatocytes were seen 48 h after hepatectomy, indicating active hepatocytes in the S/G2/M phases of the cell cycle. CONCLUSIONS: Hepatocellular regeneration is readily visualized in regenerating livers of Fucci mice. The Fucci model is an exciting tool for advanced studies of hepatocellular and liver regeneration.

Immunomodulating Nanomedicine for Cancer Therapy.

Nanomaterials offer unique advantages as drug-delivery vehicles for cancer therapeutics. For immuno-oncology applications, cancer nanomedicine should be developed beyond drug-delivery platforms. A greater emphasis on actively modulating host anticancer immunity using nanomaterials provides new avenues for developing novel cancer therapeutics.

Study of Osteocyte Behavior by High-Resolution Intravital Imaging Following Photo-Induced Ischemia.

Ischemic injuries and local hypoxia can result in osteocytes dysfunction and play a key role in the pathogenesis of avascular osteonecrosis. Conventional imaging techniques including magnetic resonance imaging (MRI) and computed tomography (CT) can reveal structural and functional changes within bony anatomy; however, characterization of osteocyte behavioral dynamics in the setting of osteonecrosis at the single cell resolution is limited. Here, we demonstrate an optical approach to study real-time osteocyte functions in vivo. Using nicotinamide adenine dinucleotide (NADH) as a biomarker for metabolic dynamics in osteocytes, we showed that NADH level within osteocytes transiently increase significantly after local ischemia through non-invasive photo-induced thrombosis of afferent arterioles followed by a steady decline. Our study presents a non-invasive optical approach to study osteocyte behavior through the modulation of local environmental conditions. Thus it provides a powerful toolkit to study cellular processes involved in bone pathologies in vivo.

Non-contiguous meningeal metastases of olfactory neuroblastoma.

Olfactory neuroblastoma (ONB) is a malignant neoplasm centered along the roof of the nasal cavity near the cribriform plate. Although metastasis of this tumor has been reported, non-contiguous spread to the dura is rare. Here, we report the largest series of intracranial meningeal metastases of ONBs from M.D. Anderson Cancer Center and the University of Toronto. The unique natural history and geographical distribution of these metastatic lesions suggest a common mechanism of tumor spread along the dural vascular arborization.

Cerebral Venous Thrombosis Associated with Intracranial Hemorrhage and Timing of Anticoagulation after Hemicraniectomy.

BACKGROUND: Cerebral venous thrombosis (CVT) is a rare cerebrovascular event that can present with headache, seizure, and focal neurological deficits. Approximately 30%-40% of patients with CVT also present with intracranial hemorrhage. Current guidelines recommend anticoagulation after CVT even in the setting of intracranial hemorrhage, but the timing of initiation is unclear. We present a case of CVT where timing of anticoagulation was unclear by current guidelines. METHODS: We conducted a literature search with search terms of "cerebral venous thrombosis," "intracranial hemorrhage," and "anticoagulation." Abstracted information included anticoagulation status and time of initiation of anticoagulation. We present a 30-year-old woman with sudden onset of right hemiplegia, global aphasia, and new-onset seizures diagnosed with left transverse and sigmoid sinus thrombosis with intraparenchymal hemorrhage. The patient was treated with endovascular thrombectomy and decompressive hemicraniectomy due to hemorrhage expansion, and anticoagulation was restarted 8 days after hemicraniectomy. RESULTS: The literature review demonstrated a wide variation of timing for anticoagulation initiation in patients with CVT and intracranial hemorrhage. Most started anticoagulation within 24 hours of admission with similar functional neurological recovery. Current guidelines on the treatment of CVT, even with intracranial hemorrhage, recommend anticoagulation. Most reports in the literature state initiation of anticoagulation within 24 hours. However, the literature does not definitively state when to initiate anticoagulation in a patient with CVT, intracranial hemorrhage, thrombectomy, and decompressive hemicraniectomy. CONCLUSION: This case illustrates the challenge of determining when to resume anticoagulation for CVT.

Elevated risks of subsequent endometrial cancer development among breast cancer survivors with different hormone receptor status: a SEER analysis.

Estrogen receptor (ER)-positive breast cancer patients treated with tamoxifen are known to have an elevated risk of subsequent endometrial cancer. However, it is unclear if ER-negative patients also have a higher risk of endometrial cancer. This population-based study aims to evaluate whether breast cancer patients with distinctive ER and PR status possess differential risks in developing delayed endometrial malignancy. Data were obtained from the Surveillance, Epidemiology, and End Results program (1992-2009). Standardized incidence ratio (SIR) was calculated as the observed cases of endometrial cancers among breast cancer survivors compared with the expected cases in the general population. Data were stratified by latency periods, race, age, and calendar year of breast cancer diagnosis. We identified 2044 patients who developed a second primary endometrial cancer among 289,933 breast cancer survivors. The overall SIRs for subsequent endometrial cancers were increased in all of the four subtypes (ER+PR+, ER+PR-, ER-PR+, and ER-PR-) of breast cancer. SIR was increased for all latency periods except for the initial 6-11 months after breast cancer diagnosis. Stratifying by age of diagnosis, elevated SIRs in all ER/PR groups were statistically significant among patients diagnosed with breast cancer after the age of 40. Demographically, non-Hispanic whites had increased SIRs in all subtypes of breast cancer, while Hispanic whites had no statistically elevated SIRs. Here we showed that patients with invasive breast cancer have a higher risk of developing subsequent endometrial cancer regardless of ER or PR status. The increased risk among hormone receptor-negative breast cancer survivors raises concerns whether common etiological factors among these breast cancer subtypes increase the susceptibility to develop endometrial cancer. Lower threshold for routine endometrial cancer surveillance may be warranted.

Diagnostic discrepancies in malignant astrocytoma due to limited small pathological tumor sample can be overcome by IDH1 testing.

The accurate grading of malignant astrocytomas has significant prognostic and therapeutic implications. Traditional histopathological grading can be challenging due to regional tumor heterogeneity, especially in scenarios where small amounts of tissue are available for pathologic review. Here, we hypothesized that a critical tumor resection volume is needed for correct grading of astrocytomas by histopathology. For insufficient tissue sampling, IDH1 molecular testing can act as a complementary marker to improve diagnostic accuracy. Volumetric analyses were obtained using preoperative and postoperative MRI images. Histological specimens were gathered from 403 patients with malignant astrocytoma who underwent craniotomy. IDH1 status was assessed by immunohistochemistry and sequencing. Patients with >20 cubic centimeters (cc) of the total tumor volume resected on MRI have higher rate of GBM diagnosis compared to <20 cc [odds ratio (OR) 2.57, 95% confidence interval (CI) 1.6-4.06, P < 0.0001]. The rate of IDH1 status remained constant regardless of the tumor volume resected (OR 0.81, 95% CI 0.48-1.36, P < 0.43). The rate of GBM diagnosis is twofold greater for individual surgical specimen >10 cc than those of lower volume (OR 2.48, 95% CI 1.88-3.28, P < 0.0001). Overall survival for AA patients with >20 cc tumor resection on MRI is significantly better than those with <20 cc tumor resected (P < 0.05). No volume-dependent differences were observed in patients with GBM (P < 0.4), IDH1 wild type (P < 0.1) or IDH1 mutation (P < 0.88). IDH1 status should be considered when total resection volume is <20 cc based on MRI analysis and for surgical specimen <10 cc to complement histopathologic diagnosis of malignant astrocytomas. In these specimens, under-diagnosis of GBM may occur when analysis is restricted to histopathology alone.

Striking the Balance with a PD-L1×4-1BB Bispecific Antibody.

Antibody-based immune checkpoint blockade therapy has revolutionized the field of cancer immunotherapy, yet its efficacy remains limited in immunologically cold tumors. Combining checkpoint inhibitors with costimulatory agonists improves tumoricidal activity of T cells but also can lead to off-target hepatotoxicity. Although bispecific antibodies confer tumor selectivity to alleviate undesirable adverse effects, toxicity concerns persist with increased dosing. In this issue of Cancer Research, Yuwen and colleagues introduce ATG-101, a tetravalent PD-L1×4-1BB bispecific antibody with high programmed death ligand 1 (PD-L1) affinity and low 4-1BB affinity, aiming to mitigate hepatotoxicity. ATG-101 demonstrates PD-L1-dependent 4-1BB activation, leading to selective T-cell activation within the tumor microenvironment. ATG-101 exhibits potent antitumor activity, even in large, immunologically cold, and monotherapy-resistant tumor models. Single-cell RNA sequencing reveals significant shifts of immune cell populations in the tumor microenvironment from protumor to antitumor phenotypes following ATG-101 treatment. In cynomolgus monkeys, no serious cytokine storm and hepatotoxicity are observed after ATG-101 treatment, indicating a broad therapeutic window for ATG-101 in cancer treatment. This study highlights the potential of tetravalent bispecific antibodies in cancer immunotherapy, with implications for various antibody-based treatment modalities across different fields. See related article by Yuwen et al., p. 1680.

Radiation Synergizes with IL2/IL15 Stimulation to Enhance Innate Immune Activation and Antitumor Immunity.

Ionizing radiation is known to possess immune modulatory properties. However, how radiotherapy (RT) may complement with different types of immunotherapies to boost antitumor responses is unclear. In mice implanted with EO771 syngeneic tumors, NL-201 a stable, highly potent CD25-independent agonist to IL2 and IL15 receptors with enhanced affinity for IL2Rßγ was given with or without RT. Flow analysis and Western blot analysis was performed to determine the mechanisms involved. STING (-/-) and CD11c+ knockout mice were implanted with EO771 tumors to confirm the essential signaling and cell types required to mediate the effects seen. Combination of RT and NL-201 to enhance systemic immunotherapy with an anti-PD-1 checkpoint inhibitor was utilized to determine tumor growth inhibition and survival, along characterization of tumor microenvironment as compared with all other treatment groups. Here, we showed that RT, synergizing with NL-201 produced enhanced antitumor immune responses in murine breast cancer models. When given together, RT and NL-201 enhanced activation of the cytosolic DNA sensor cyclic GMP-AMP synthase-stimulator of IFN genes (cGAS-STING) pathway, resulting in increased type I IFN production in dendritic cells (DC), and consequently greater tumor infiltration and more efficient priming of antigen-specific T cells. The immune stimulatory mechanisms triggered by NL-201 and RT resulted in superior tumor growth inhibition and survival benefit in both localized and metastatic cancers. Our results support further preclinical and clinical investigation of this novel synergism regimen in locally advanced and metastatic settings.

Engineering therapeutical extracellular vesicles for clinical translation.

Cell-based therapies are revolutionizing medicine by replacing or modifying dysfunctional cells with healthy cells or engineered derivatives, offering disease reversal and cure. One promising approach is using cell-derived extracellular vesicles (EVs), which offer therapeutic benefits similar to cell transplants without the biosafety risks. Although EV applications face challenges like limited production, inadequate therapeutic loading, and poor targeting efficiency, recent advances in bioengineering have enhanced their effectiveness. Herein, we summarize technological breakthroughs in EV bioengineering over the past 5 years, highlighting their improved therapeutic functionalities and potential clinical prospects. We also discuss biomanufacturing processes, regulation, and safety considerations for bioengineered EV therapies, emphasizing the significance of establishing robust frameworks to ensure translation capability, safety, and therapeutic effectiveness for successful clinical adoption.

New avenues for cancer immunotherapy: Cell-mediated drug delivery systems.

Cancer research has become increasingly complex over the past few decades as knowledge of the heterogeneity of cancer cells, their proliferative ability, and their tumor microenvironments has become available. Although conventional therapies remain the most compelling option for cancer treatment to date, immunotherapy is a promising way to harness natural immune defenses to target and kill cancer cells. Cell-mediated drug delivery systems (CDDSs) have been an active line of research for enhancing the therapeutic efficacy and specificity of cancer immunotherapy. These systems can be tailored to different types of immune cells, allowing immune evasion and accumulation in the tumor microenvironment. By enabling the targeted delivery of therapeutic agents such as immune stimulants, cytokines, antibodies, and antigens, CDDSs have improved the survival of some patients with cancer. This review summarizes the research status of CDDSs, with a focus on their underlying mechanisms of action, biology, and clinical applications. We also discuss opportunities and challenges for implementation of CDDSs into mainstream cancer immunotherapy.

Bio-integrated scaffold facilitates large bone regeneration dominated by endochondral ossification.

Repair of large bone defects caused by severe trauma, non-union fractures, or tumor resection remains challenging because of limited regenerative ability. Typically, these defects heal through mixed routines, including intramembranous ossification (IMO) and endochondral ossification (ECO), with ECO considered more efficient. Current strategies to promote large bone healing via ECO are unstable and require high-dose growth factors or complex cell therapy that cause side effects and raise expense while providing only limited benefit. Herein, we report a bio-integrated scaffold capable of initiating an early hypoxia microenvironment with controllable release of low-dose recombinant bone morphogenetic protein-2 (rhBMP-2), aiming to induce ECO-dominated repair. Specifically, we apply a mesoporous structure to accelerate iron chelation, this promoting early chondrogenesis via deferoxamine (DFO)-induced hypoxia-inducible factor-1α (HIF-1α). Through the delicate segmentation of click-crosslinked PEGylated Poly (glycerol sebacate) (PEGS) layers, we achieve programmed release of low-dose rhBMP-2, which can facilitate cartilage-to-bone transformation while reducing side effect risks. We demonstrate this system can strengthen the ECO healing and convert mixed or mixed or IMO-guided routes to ECO-dominated approach in large-size models with clinical relevance. Collectively, these findings demonstrate a biomaterial-based strategy for driving ECO-dominated healing, paving a promising pave towards its clinical use in addressing large bone defects.

Regulation of cerebral blood flow boosts precise brain targeting of vinpocetine-derived ionizable-lipidoid nanoparticles.

Despite advances in active drug targeting for blood-brain barrier penetration, two key challenges persist: first, attachment of a targeting ligand to the drug or drug carrier does not enhance its brain biodistribution; and second, many brain diseases are intricately linked to microcirculation disorders that significantly impede drug accumulation within brain lesions even after they cross the barrier. Inspired by the neuroprotective properties of vinpocetine, which regulates cerebral blood flow, we propose a molecular library design centered on this class of cyclic tertiary amine compounds and develop a self-enhanced brain-targeted nucleic acid delivery system. Our findings reveal that: (i) vinpocetine-derived ionizable-lipidoid nanoparticles efficiently breach the blood-brain barrier; (ii) they have high gene-loading capacity, facilitating endosomal escape and intracellular transport; (iii) their administration is safe with minimal immunogenicity even with prolonged use; and (iv) they have potent pharmacologic brain-protective activity and may synergize with treatments for brain disorders as demonstrated in male APP/PS1 mice.

Age-associated disparity in phagocytic clearance affects the efficacy of cancer nanotherapeutics.

Nanomedicines have been approved to treat multiple human diseases. However, clinical adoption of nanoformulated agents is often hindered by concerns about hepatic uptake and clearance, a process that is not fully understood. Here we show that the antitumour efficacy of cancer nanomedicine exhibits an age-associated disparity. Tumour delivery and treatment outcomes are superior in old versus young mice, probably due to an age-related decline in the ability of hepatic phagocytes to take up and remove nanoparticles. Transcriptomic- and protein-level analysis at the single-cell and bulk levels reveals an age-associated decrease in the numbers of hepatic macrophages that express the scavenger receptor MARCO in mice, non-human primates and humans. Therapeutic blockade of MARCO is shown to decrease the phagocytic uptake of nanoparticles and improve the antitumour effect of clinically approved cancer nanotherapeutics in young but not aged mice. Together, these results reveal an age-associated disparity in the phagocytic clearance of nanotherapeutics that affects their antitumour response, thus providing a strong rationale for an age-appropriate approach to cancer nanomedicine.

Synthetic cationic helical polypeptides for the stimulation of antitumour innate immune pathways in antigen-presenting cells.

Intracellular DNA sensors regulate innate immunity and can provide a bridge to adaptive immunogenicity. However, the activation of the sensors in antigen-presenting cells (APCs) by natural agonists such as double-stranded DNAs or cyclic nucleotides is impeded by poor intracellular delivery, serum stability, enzymatic degradation and rapid systemic clearance. Here we show that the hydrophobicity, electrostatic charge and secondary conformation of helical polypeptides can be optimized to stimulate innate immune pathways via endoplasmic reticulum stress in APCs. One of the three polypeptides that we engineered activated two major intracellular DNA-sensing pathways (cGAS-STING (for cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes) and Toll-like receptor 9) preferentially in APCs by promoting the release of mitochondrial DNA, which led to the efficient priming of effector T cells. In syngeneic mouse models of locally advanced and metastatic breast cancers, the polypeptides led to potent DNA-sensor-mediated antitumour responses when intravenously given as monotherapy or with immune checkpoint inhibitors. The activation of multiple innate immune pathways via engineered cationic polypeptides may offer therapeutic advantages in the generation of antitumour immune responses.

Response of treatment-naive brain metastases to stereotactic radiosurgery.

With improvements in survival for patients with metastatic cancer, long-term local control of brain metastases has become an increasingly important clinical priority. While consensus guidelines recommend surgery followed by stereotactic radiosurgery (SRS) for lesions >3 cm, smaller lesions (≤3 cm) treated with SRS alone elicit variable responses. To determine factors influencing this variable response to SRS, we analyzed outcomes of brain metastases ≤3 cm diameter in patients with no prior systemic therapy treated with frame-based single-fraction SRS. Following SRS, 259 out of 1733 (15%) treated lesions demonstrated MRI findings concerning for local treatment failure (LTF), of which 202 /1733 (12%) demonstrated LTF and 54/1733 (3%) had an adverse radiation effect. Multivariate analysis demonstrated tumor size (>1.5 cm) and melanoma histology were associated with higher LTF rates. Our results demonstrate that brain metastases ≤3 cm are not uniformly responsive to SRS and suggest that prospective studies to evaluate the effect of SRS alone or in combination with surgery on brain metastases ≤3 cm matched by tumor size and histology are warranted. These studies will help establish multi-disciplinary treatment guidelines that improve local control while minimizing radiation necrosis during treatment of brain metastasis ≤3 cm.

Targeting phagocytosis to enhance antitumor immunity.

Many patients with metastatic or treatment-resistant cancer have experienced improved outcomes after immunotherapy that targets adaptive immune checkpoints. However, innate immune checkpoints, which can hinder the detection and clearance of malignant cells, are also crucial in tumor-mediated immune escape and may also serve as targets in cancer immunotherapy. In this review, we discuss the current understanding of immune evasion by cancer cells via disruption of phagocytic clearance, and the potential effects of blocking phagocytosis checkpoints on the activation of antitumor immune responses. We propose that a more effective combination immunotherapy strategy could be to exploit tumor-intrinsic processes that inhibit key innate immune surveillance processes, such as phagocytosis, and incorporate both innate and adaptive immune responses for treating patients with cancer.