Although interest and funding in nanotechnology for oncological applications is thriving, translating these novel therapeutics through the earliest stages of preclinical assessment remains challenging. Upon intravenous administration, nanomaterials interact with constituents of the blood inducing a wide range of associated immunotoxic effects. The literature on the immunological interactions of nanomaterials is vast and complicated. A small change in a particular characteristic of a nanomaterial (e.g., size, shape, or charge) can have a significant effect on its immunological profile in vivo, and poor selection of specific assays for establishing these undesirable effects can overlook this issue until the latest stages of preclinical assessment. This work describes the current literature on unintentional immunological effects associated with promising cancer nanomaterials (liposomes, dendrimers, mesoporous silica, iron oxide, gold, and quantum dots) and puts focus on what is missing in current preclinical evaluations. Opportunities for avoiding or limiting immunotoxicity through efficient preclinical assessment are discussed, with an emphasis placed on current regulatory views and requirements. Careful consideration of these issues will ensure a more efficient preclinical assessment of cancer nanomedicines, enabling a smoother clinical translation with less failures in the future.

Heat has been used to treat tumors for thousands of years. There are reports of the Egyptians and Greek philosophers using such treatments as far back as 3000 BC and 500 BC respectively for various solid tumors. Albeit, in these cases, the treatment was not very controlled and consisted of hot sticks or blades placed against tissue in order to thermally ablate the tumor. It was not until recent times that the application of heat through various mediums enabled a more controlled, localized, and consistent method of treating tumors. While the therapeutic potential of this treatment has become more apparent, the mechanisms related to its efficacy are only recently beginning to surface. This review discusses the evidence associated with the effects of localized heat on the hallmarks of cancer. Key literature describing modulations to vasculature, cell viability, DNA damage and repair, metabolism, immune system, and tumor metastasis in response to heat will be reviewed along with considerations for its optimal implementation in the clinic to enhance the efficacy of conventional treatments.

Magnetic hyperthermia involves the use of iron oxide nanoparticles to generate heat in tumours following stimulation with alternating magnetic fields. In recent times, this treatment has undergone numerous clinical trials in various solid malignancies and subsequently achieved clinical approval to treat glioblastoma and prostate cancer in 2011 and 2018, respectively. However, despite recent clinical advances, many questions remain with regard to the underlying mechanisms involved in this therapy. One such query is whether intracellular or extracellular nanoparticles are necessary for treatment efficacy. Herein, we compare the effects of intracellular and extracellular magnetic hyperthermia in BxPC-3 cells to determine the differences in efficacy between both. Extracellular magnetic hyperthermia at temperatures between 40–42.5 °C could induce significant levels of necrosis in these cells, whereas intracellular magnetic hyperthermia resulted in no change in viability. This led to a discussion on the overall relevance of intracellular nanoparticles to the efficacy of magnetic hyperthermia therapy.

Pronounced T cell exhaustion characterizes immunosuppressive tumors, with the tumor microenvironment (TME) employing multiple mechanisms to elicit this suppression. Traditional immunotherapies, such as immune checkpoint blockade, often fail due to their focus primarily on T cells. To overcome this, we utilized a proinflammatory cytokine, interleukin (IL)-12, that re-wires the immunosuppressive TME by inducing T cell effector function while also repolarizing immunosuppressive myeloid cells. Due to toxicities observed with systemic administration of this cytokine, we utilized lipid nanoparticles encapsulating mRNA encoding IL-12 for intratumoral injection. This strategy has been proven safe and tolerable in early clinical trials for solid malignancies. We report an unprecedented loss of exhausted T cells and the emergence of an activated phenotype in murine pancreatic ductal adenocarcinoma (PDAC) treated with stereotactic body radiation therapy (SBRT) and IL-12mRNA. Our mechanistic findings reveal that each treatment modality contributes to the T cell response differently, with SBRT expanding the T cell receptor repertoire and IL-12mRNA promoting robust T cell proliferation and effector status. This distinctive T cell signature mediated marked growth reductions and long-term survival in local and metastatic PDAC models. This is the first study of its kind combining SBRT with IL-12mRNA and provides a promising new approach for treating this aggressive malignancy.

Ionizing radiation (IR) is used to treat 50% of cancers. While the cytotoxic effects related to DNA damage with IR have been known since the early 20th century, the role of the immune system in the treatment response is still yet to be fully determined. IR can induce immunogenic cell death (ICD), which activates innate and adaptive immunity against the cancer. It has also been widely reported that an intact immune system is essential to IR efficacy. However, this response is typically transient, and wound healing processes also become upregulated, dampening early immunological efforts to overcome the disease. This immune suppression involves many complex cellular and molecular mechanisms that ultimately result in the generation of radioresistance in many cases. Understanding the mechanisms behind these responses is challenging as the effects are extensive and often occur simultaneously within the tumor. Here, we describe the effects of IR on the immune landscape of tumors. ICD, along with myeloid and lymphoid responses to IR, are discussed, with the hope of shedding light on the complex immune stimulatory and immunosuppressive responses involved with this cornerstone cancer treatment. Leveraging these immunological effects can provide a platform for improving immunotherapy efficacy in the future.

Background: Pancreatic cancer is a deadly cancer with a 5-year survival rate less than 10%. Only 20% of patients are eligible to receive surgery at diagnosis. Hence, new therapies are needed to improve outcomes for non-surgical candidates. Thermal ablation techniques can offer a non-invasive alternative to surgery.Aim: The aim of this review is to map the literature for the use of thermal ablative techniques: Radiofrequency ablation (RFA), High-intensity focused ultrasound (HIFU), Microwave ablation (MWA), and Laser ablation (LA) in the management of patients with PC.Methods: A search strategy was applied to PUBMED and EMBASE using keywords concerning pancreatic cancer, radiofrequency ablation, ultrasound ablation, laser ablation, and microwave ablation. The studies that fit this inclusion criteria were summarized in table format and results reviewed for interpretation.Results: 72 clinical studies were included. Most of the included studies related to RFA (n=35) and HIFU (n=27). The most common study design was retrospective (n=33). Only 3 randomized control trials (RCT) were included, all of which related to RFA. Safety outcomes were reported in 53 of the 72 studies, and survival outcomes were reported in 39. Statistically significant survival benefits were demonstrated in 11 studies.Conclusion: The evidence for the benefit of MWA and LA in PC patients is limited. RFA and HIFU are safe and feasible therapies to be used in PC patients. Further RCTs where thermal techniques are standardized and reported are necessary in the future to elucidate thermal ablation’s clinical utility, and before an evidence-based decision on its routine use in PC management can be considered.