Cancer immunotherapies targeting adaptive immune checkpoints have substantially improved patient outcomes across multiple metastatic and treatment-refractory cancer types. However, emerging studies ...have demonstrated that innate immune checkpoints, which interfere with the detection and clearance of malignant cells through phagocytosis and suppress innate immune sensing, also have a key role in tumour-mediated immune escape and might, therefore, be potential targets for cancer immunotherapy. Indeed, preclinical studies and early clinical data have established the promise of targeting phagocytosis checkpoints, such as the CD47-signal-regulatory protein α (SIRPα) axis, either alone or in combination with other cancer therapies. In this Review, we highlight the current understanding of how cancer cells evade the immune system by disrupting phagocytic clearance and the effect of phagocytosis checkpoint blockade on induction of antitumour immune responses. Given the role of innate immune cells in priming adaptive immune responses, an improved understanding of the tumour-intrinsic processes that inhibit essential immune surveillance processes, such as phagocytosis and innate immune sensing, could pave the way for the development of highly effective combination immunotherapy strategies that modulate both innate and adaptive antitumour immune responses.
Restoration of dysfunctional tumor vasculature can reestablish the pressure gradient between intravascular and interstitial space that is essential for transporting nanomedicines into solid tumors. ...Morphologic and functional normalization of tumor vessels improves tissue perfusion to facilitate intratumoral nanoparticle delivery. However, this remodeling process also reduces tumor vessel permeability, which can impair nanoparticle transport. Although nanoparticles sized below 10 nm maximally benefited from tumor vessel normalization therapy for enhanced nanomedicine delivery, the small particle size severely limits its applicability. Here, we show that intermediate-sized nanoparticles (20–40 nm) can also benefit from tumor vasculature remodeling. We demonstrate that a window of opportunity exists for a two-stage transport strategy of different nanoparticle sizes. Overall, tumor vessel remodeling enhances the transvascular delivery of intermediate-size nanoparticles of up to 40 nm. Once within the tumor matrix, however, smaller nanoparticles experience a significantly lesser degree of diffusional hindrance, resulting in a more homogeneous distribution within the tumor interstitium. These findings suggest that antiangiogenic therapy and nanoparticle design can be combined in a multistage fashion, with two sets of size-inclusion criteria, to achieve optimal nanomedicine delivery into solid tumors.
The vasculature of tumours is highly abnormal and dysfunctional. Consequently, immune effector cells have an impaired ability to penetrate solid tumours and often exhibit compromised functions. ...Normalization of the tumour vasculature can enhance tissue perfusion and improve immune effector cell infiltration, leading to immunotherapy potentiation. However, recent studies have demonstrated that the stimulation of immune cell functions can also help to normalize tumour vessels. In this Opinion article, we propose that the reciprocal regulation between tumour vascular normalization and immune reprogramming forms a reinforcing loop that reconditions the tumour immune microenvironment to induce durable antitumour immunity. A deeper understanding of these pathways could pave the way for identifying new biomarkers and developing more effective combination treatment strategies for patients with cancer.
Nanomedicine offers unique advantages in treating human cancers. However, physiological and pathological barriers within normal and disease tissues, which are highly variable among individuals, often ...hinder its effectiveness. The body possesses specific innate responses to nanoparticles (NPs), which when combined with unique pathophysiological signatures in the tumor microenvironment, can severely limit the utility of nanomedicine in the oncological setting. Furthermore, with the successes of cancer immunotherapies, understanding nanoimmune interactions and developing immune-smart cancer nanomedicine that can take advantage of the body's immune functions will increasingly become clinically relevant. Therefore, a better understanding of the important native and acquired biological processes that dictate the fate of nanomedicine is integral to developing more effective individualized platforms for treating cancer patients.
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.
Nanostructures of different sizes, shapes and material properties have many applications in biomedical imaging, clinical diagnostics and therapeutics. In spite of what has been achieved so far, a ...complete understanding of how cells interact with nanostructures of well-defined sizes, at the molecular level, remains poorly understood. Here we show that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization. The binding and activation of membrane receptors and subsequent protein expression strongly depend on nanoparticle size. Although all nanoparticles within the 2-100 nm size range were found to alter signalling processes essential for basic cell functions (including cell death), 40- and 50-nm nanoparticles demonstrated the greatest effect. These results show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects. The findings presented here may assist in the design of nanoscale delivery and therapeutic systems and provide insights into nanotoxicity.
The cytosolic innate immune sensor cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway is crucial for priming adaptive antitumour immunity through antigen-presenting cells ...(APCs). Natural agonists, such as cyclic dinucleotides (CDNs), activate the cGAS-STING pathway, but their clinical translation is impeded by poor cytosolic entry and serum stability, low specificity and rapid tissue clearance. Here we developed an ultrasound (US)-guided cancer immunotherapy platform using nanocomplexes composed of 2'3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) electrostatically bound to biocompatible branched cationic biopolymers that are conjugated onto APC-targeting microbubbles (MBs). The nanocomplex-conjugated MBs engaged with APCs and efficiently delivered cGAMP into the cytosol via sonoporation, resulting in activation of cGAS-STING and downstream proinflammatory pathways that efficiently prime antigen-specific T cells. This bridging of innate and adaptive immunity inhibited tumour growth in both localized and metastatic murine cancer models. Our findings demonstrate that targeted local activation of STING in APCs under spatiotemporal US stimulation results in systemic antitumour immunity and improves the therapeutic efficacy of checkpoint blockade, thus paving the way towards novel image-guided strategies for targeted immunotherapy of cancer.
Immunotherapy is known to be clinically beneficial for cancer patients and in many cases represents the new standard of care. Because of this success, the interest in integrating nanomedicine with ...cancer immunotherapy to further improve clinical response and toxicity profiles has grown. However, unlike conventional systemic therapies, which are directly cytotoxic to tumour cells, cancer immunotherapy relies on the host's immune system to generate tumouricidal effects. As such, proper design of cancer immune nanomedicine requires scrutiny of tumours' intrinsic and extrinsic factors that may impact host antitumour immunity. Here, we highlight key parameters that differentiate cancer immunotherapy from conventional cytotoxic agents, and we discuss their implications for designing preclinical cancer immune nanomedicine studies. We emphasize that these factors, including intratumoural genomic heterogeneity, commensal diversity, sexual dimorphism and biological ageing, which were largely ignored in traditional cancer nanomedicine experiments, should be carefully considered and incorporated into cancer immune nanomedicine investigations given their critical involvement in shaping the body's antitumour immune responses.
A major rate-limiting step in developing more effective immunotherapies for GBM is our inadequate understanding of the cellular complexity and the molecular heterogeneity of immune infiltrates in ...gliomas. Here, we report an integrated analysis of 201,986 human glioma, immune, and other stromal cells at the single cell level. In doing so, we discover extensive spatial and molecular heterogeneity in immune infiltrates. We identify molecular signatures for nine distinct myeloid cell subtypes, of which five are independent prognostic indicators of glioma patient survival. Furthermore, we identify S100A4 as a regulator of immune suppressive T and myeloid cells in GBM and demonstrate that deleting S100a4 in non-cancer cells is sufficient to reprogram the immune landscape and significantly improve survival. This study provides insights into spatial, molecular, and functional heterogeneity of glioma and glioma-associated immune cells and demonstrates the utility of this dataset for discovering therapeutic targets for this poorly immunogenic cancer.
Tumour cell phagocytosis by antigen presenting cells (APCs) is critical to the generation of antitumour immunity. However, cancer cells can evade phagocytosis by upregulating anti-phagocytosis ...molecule CD47. Here, we show that CD47 blockade alone is inefficient in stimulating glioma cell phagocytosis. However, combining CD47 blockade with temozolomide results in a significant pro-phagocytosis effect due to the latter's ability to induce endoplasmic reticulum stress response. Increased tumour cell phagocytosis subsequently enhances antigen cross-presentation and activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) in APCs, resulting in more efficient T cell priming. This bridging of innate and adaptive responses inhibits glioma growth, but also activates immune checkpoint. Sequential administration of an anti-PD1 antibody overcomes this potential adaptive resistance. Together, these findings reveal a dynamic relationship between innate and adaptive immune regulation in tumours and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
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