Radiotherapy is a standard therapy for oral squamous cell carcinoma (OSCC) with immunomodulatory potential. Due to high lymphocyte radiosensitivity, partial tumor-volume irradiation (pIR), targeting only part of the tumor, is being explored for immunomodulation. This study compared the effects of whole tumor-volume irradiation (IR) and pIR, targeting approximately 50 % of the tumor volume, in combination with anti-PD-1 immune checkpoint inhibitors (ICI). The therapeutic efficacy of a single 15 Gy IR or pIR dose combined with anti-PD-1 ICI was evaluated in two immune cold murine OSCC models: human papillomavirus (HPV)-negative MOC1 and HPV-positive MOC1-HPV K1 stably expressing HPV-16 oncogenes E6/E7. Additionally, immune cell populations in the tumor microenvironment (TME) were analyzed using flow cytometry. Both IR and pIR induced transient immune cell infiltration in the TME. However, pIR led to significantly lower tumor growth inhibition than IR. While IR + ICI failed to improve survival compared to IR alone, pIR + ICI significantly prolonged survival compared to pIR alone in the MOC1 model, along with increase in cytotoxic T cell infiltration. In the MOC1-HPV K1 model, responses varied. Responding tumors were enriched with effector memory T cells, whereas non-responders exhibited increased neutrophil (MDSCs) and monocyte-derived dendritic cells infiltration. The study indicates that while pIR has immunomodulatory potential, its effects are comparable to IR in the tested settings. Further research is needed to optimize dosing and scheduling for pIR and anti-PD-1 ICI. Additionally, combination with other immunotherapies could be explored in further studies to enhance treatment efficacy in immune cold OSCC models.

External beam radiation therapy (RT) is a cornerstone of modern cancer management, being utilized in both curative and palliative settings due to its safety, efficacy, and widespread availability. A primary biological effect of RT is DNA damage, which leads to significant cytostatic and cytotoxic effects. Importantly, malignant cells possess a limited capacity for DNA repair compared to normal cells, and when combined with irradiation techniques that minimize damage to healthy tissues, this creates an advantageous therapeutic window. However, the clinical effectiveness of RT also appears to involve both direct and indirect interactions between RT and non-transformed components of the tumoral ecosystem, particularly immune cells. In this review, we describe the molecular and cellular mechanisms by which irradiated cancer cells modify the immunological tumor microenvironment and how such changes ultimately impact tumor growth.

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER+) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER+ breast cancer patients.

The signaling mechanisms of nucleotides and nucleosides have been extensively studied over the past decades in various conditions affecting distinct organs and tissues. It is well-established that purinergic receptors are expressed in healthy tissues, with expression levels often increasing under pathological conditions. These receptors play crucial roles in numerous physiological and pathological processes, including inflammation, tissue repair, and cellular signaling. However, the purinergic context in the esophagus and its associated pathologies remains poorly understood, representing a significant gap in current knowledge. In this review, we compiled and analyzed the available data on the involvement of P2 purinergic receptors in esophageal diseases, such as gastroesophageal reflux disease and esophageal carcinoma. Specifically, we discuss the pharmacological modulation, functional characterization, and expression patterns of these receptors in various esophageal cell lines and immune tissue samples, under both healthy and pathological conditions. Understanding the mechanisms of action and signaling pathways involving P2 purinergic receptors in the esophagus can offer valuable insights into their biological roles and emphasize their potential as therapeutic targets for future clinical applications.

Radiotherapy (RT) can trigger immunogenic cell death (ICD) in tumor cells and release adenosine triphosphate (ATP) to activate antitumor immunity. However, the formation of immunosuppressive adenosine (ADO) mediated by ectonucleotidases including CD39 and CD73, can exacerbate the immunosuppressive effects. Herein, a radiosensitizer-based metal-organic framework (MOF) composed of bismuth (Bi) and ellagic acid (EA) was synthesized in situ on the surface of Escherichia coli Nissle 1917 (EcN) to serve as a carrier for the CD39 inhibitor sodium polyoxotungstate (POM-1). This therapeutic platform, acting as a radiosensitizer, significantly enhances cytotoxicity against tumor cells while effectively inducing ICD and releasing high concentrations of ATP. Subsequently, the released POM-1 increases the levels of pro-inflammatory extracellular ATP while preventing tumor immunosuppression caused by the accumulation of ADO. Additionally, as a natural immune adjuvant, EcN further promotes the maturation of dendritic cells (DCs) and the infiltration of cytotoxic T lymphocytes (CTLs). As a result, such treatment initiates the destruction of established tumor growth and induces strong abscopal effects, leading to a significant inhibition of tumor metastases. This strategy presents a bacterial-based biohybrid system that facilitates RT-induced ICD while simultaneously limiting the degradation of ATP into ADO, thereby achieving sustained anti-tumor immunity.

Breast cancer is the most prevalent cancer among women worldwide, with various subtypes that require distinct treatment approaches. Among these, Triple-Negative Breast Bancer (TNBC) is recognized as the most aggressive form, often associated with poor prognosis due to its lack of targeted therapeutic options. This review specifically focuses on Radiotherapy (RT) as a treatment modality for TNBC, evaluating recent advancements and ongoing challenges, particularly the issue of radioresistance. RT remains an essential part in the management of breast cancer, including TNBC. Over the years, multiple improvements have been made to enhance RT effectiveness and minimize resistance. The introduction of advanced techniques such as Stereotactic Body Radiation Therapy (SBRT) and Stereotactic Radiosurgery (SRS) has significantly improved precision and reduced toxicity. More recently, proton radiation therapy, a novel RT modality, has been introduced, offering enhanced dose distribution and reducing damage to surrounding healthy tissues. Despite these technological advancements, a subset of TNBC patients continues to exhibit resistance to RT, leading to recurrence and poor treatment outcomes. To overcome radioresistance, there is an increasing interest in combining RT with targeted therapeutic agents that sensitize cancer cells to radiation. Radiosensitizing drugs have been explored to enhance the efficacy of RT by making cancer cells more susceptible to radiation-induced damage. Potential candidates include DNA damage repair inhibitors, immune checkpoint inhibitors, and small-molecule targeted therapies that interfere with key survival pathways in TNBC cells. In conclusion, while RT remains a crucial modality for TNBC treatment, radioresistance remains a significant challenge. Future research should focus on optimizing RT techniques while integrating radiosensitizing agents to improve treatment efficacy. By combining RT with targeted drug therapy, a more effective and personalized treatment approach can be developed, ultimately improving patient outcomes and reducing recurrence rates in TNBC.

The activation of the cGAS-STING pathway occurs when tumor cell DNA is damaged by ionizing radiation. Once triggered, this pathway reshapes the tumor immune microenvironment by promoting the maturation, activation, polarization, and immune-killing capacity of immune cells, as well as by inducing the release of interferons and the expression of immune-related genes. In addition, the gut microbiota and various mechanisms of programmed cell death interact with the cGAS-STING pathway, further influencing its function in remodeling the immune microenvironment after radiotherapy. Therefore, investigating the mechanisms of the cGAS-STING pathway in reshaping the tumor immune microenvironment post-radiotherapy can not only optimize the efficacy of combined radiotherapy and immunotherapy but also provide new research directions and potential targets for cancer treatment.

Oncolytic viruses (OVs) are natural or recombinant viruses that can directly lyse tumor cells without damaging normal cells. They enhance anti-tumor immunity by releasing antigens and activating inflammatory responses within the tumor microenvironment (TME). This offers a new therapeutic approach for MPE and solid tumors. This review discusses the progress of OVs administered via intrapleural and intratumoral routes, emphasizing their potential in MPE treatment and the challenges posed by the complex intrapleural environment, which affects the direct interaction between OVs, tumor cells, and immune cells. This review also discusses the regulatory barriers, safety concerns and accessibility of oncolytic virus therapy.

Radiotherapy (RT) is a key treatment modality in cancer therapy, utilizing high-energy radiation to directly kill tumor cells. Recent research has increasingly highlighted RT's potential to indirectly enhance antitumor immunity. However, this immune activation alone often fails to generate sustained systemic antitumor responses. In this study, we aimed to investigate the antitumor effects of combining cholesterolized toll-like receptor 7 (TLR7) agonist liposomes, specifically 1V209-Cho-Lip, with RT.

Mouse tumor models were used to assess the impact of combining 1V209-Cho-Lip with RT on tumor progression and modification of the tumor microenvironment. In vitro, primary mouse bone marrow-derived dendritic cells (BMDCs) were utilized to investigate changes in function and the activated pathways through RNA sequencing. Additionally, we explored the role of oxidized mitochondrial DNA (ox-mtDNA) released from irradiated tumor cells as a damage-associated molecular pattern in modulating immune responses. The involvement of interleukin-1β (IL-1β) and the inflammasome pathway in the antitumor efficacy of the combined treatment was evaluated using Il-1β-/- and cysteinyl aspartate specific proteinase 1 knockout (Casp1-/-) mouse models.

The combination of 1V209-Cho-Lip and RT significantly inhibited tumor growth and induced antitumor immunity in tumor models. This combination therapy enhanced maturation, antigen presentation and IL-1β secretion of dendritic cells (DCs) in vitro. Ox-mtDNA released from irradiated tumor cells synergized with 1V209-Cho-Lip to activate the inflammasome pathway in DCs. The antitumor effect of the combined therapy was significantly reduced in Il-1β-/- and Casp1-/- mice.

This study suggests that the combination of 1V209-Cho-Lip with RT might be a promising antitumor strategy and further studies are warranted to explore the clinical relevance of this combination therapy.

Immunogenic cell death (ICD) has attracted enormous attention over the past decade due to its unique characteristics in cancer cell death and its role in activating innate and adaptive immune responses against tumours. Many efforts have been dedicated to screening, identifying and discovering ICD inducers, resulting in the validation of several based on metal complexes. In this review, we provide a comprehensive summary of current metal-based ICD inducers, their molecular mechanisms for triggering ICD initiation and subsequent protective antitumour immune responses, along with considerations for validating ICD both in vitro and in vivo. We also aim to offer insights into the future development of metal complexes with enhanced ICD-inducing properties and their applications in potentiating antitumour immunity.

Radiation therapy can be categorised by particle type into photon, proton and heavy ion therapies. Proton radiotherapy is highlighted due to its unique physical properties, such as the Bragg peak and minimal exit dose, which offer superior dose distribution. This makes proton radiotherapy especially advantageous for treating tumours near vital organs with complex structures, such as gliomas near the brain, nasopharyngeal carcinoma near the brainstem and mediastinal tumours near the heart. Proton irradiation can induce distant effects through immunogenicity within the target area. The reduced low-dose zone outside the target provides better lymphatic system protection and immune benefits. Additionally, combining proton radiotherapy with immunotherapy may offer further biological advantages. These features make proton radiotherapy a promising option in cancer treatment. This article may aid in the understanding of proton radiotherapy and its immune effects and lead to new effective options for tumour treatment.

Immunogenic cell death (ICD), a type of regulatory cell death, plays an important role in activating the adaptive immune response. Activation of the tumor-specific immune response is accompanied by the cell surface exposure of calreticulin and heat-shock proteins, the secretion of adenosine triphosphate, and the release of high mobility group box-1. In this review, we summarize and classify the latest types of ICD inducers and their molecular mechanisms, and discuss the effects and potential applications of inducing ICD by chemotherapy drugs, targeted drugs, and oncolytic viruses in clinical research. We also explore the potential role of epigenetic modifiers in the induction of ICD, and clarify the synergistic anti-tumor effects of nano-pulse stimulation, radiosensitizers for radiotherapy, photosensitizers for photodynamic therapy, photothermal therapy, and other physical stimulation, combined with radiotherapy and chemotherapy induced-ICD, in multimodal immunotherapy. In addition, we elucidate the molecular mechanism of ICD in detail, including the calcium imbalance, mitochondrial stress, and the interactions in the tumor microenvironment. Ultimately, this review aims to offer deeper insight into the factors and mechanisms of ICD induction and provide a theoretical basis for the future development of ICD-based immunotherapy.

The combination of radiotherapy and immunotherapy exerts synergistic antitumor in a range of human cancers, and also in esophageal cancer. Radiotherapy-induced tumor immune microenvironment (TIME) reprogramming is an essential basis for the synergistic antitumor between radiotherapy and immunotherapy. Radiotherapy can induce autophagy in tumor cells and immune cells of TIME, and autophagy activation is involved in the modification of immunological characteristics of TIME. The TIME landscape of esophageal cancer, especially ESCC, can be affected by radiotherapy or autophagy regulation. In this review, we depicted that local radiotherapy-induced autophagy could promote the maturation, migration, infiltration, and function of immune cells by complicated mechanisms to make TIME from immune "cold" to "hot", resulting in the synergistic antitumor of RT and IO. We argue that unraveling the relevance of radiotherapy-initiated autophagy to driving radiotherapy reprogramming TIME will open new ideas to explore new targets or more efficiently multimodal therapeutic interventions in ESCC.

CD19-targeting chimeric antigen receptor T cells (CART19) have demonstrated significant effectiveness in treating relapsed or refractory large B-cell lymphoma (LBCL). However, they often fail to sustain durable remissions in more than half of all treated patients. Therefore, there is an urgent need to identify approaches to enhance CART19 efficacy. Here, we studied the impact of low-dose radiation on CART19 activity in vitro and find that radiation enhances the cytotoxicity of CART19 against LBCL by upregulating death receptors. Disrupting the FAS receptor diminishes this benefit, indicating that this pathway plays an important role in enhancing the cytotoxic effects of CAR T cells. To further validate these findings, we conducted in vivo studies using a lymphoma syngeneic mouse model delivering total body irradiation (TBI). We observed that delivering TBI at a single dose of 1Gy prior to CAR T cell infusion significantly improved CART19-mediated tumor elimination and increased overall survival rates. Importantly, we characterized several important effects of TBI, including enhanced lymphodepletion, improved T cell expansion and persistence, better intra-tumoral migration, and a more favorable, anti-tumor phenotypic composition of the T cells. In summary, for the first time, we have demonstrated preclinically that administering TBI before CART19 infusion significantly accelerates tumor elimination and improves overall survival. This approach holds promise for translation into clinical practice and serves as a valuable foundation for further research to enhance outcomes for patients receiving CART19 treatment.

Radiotherapy both promotes and antagonises tumour immune recognition. Some clinical studies show improved patient outcomes when immunotherapies are integrated with radiotherapy. Safe, greater than additive, clinical response to the combination is limited to a subset of patients, however, and how radiotherapy can best be combined with immunotherapies remains unclear. The National Cancer Institute-Immuno-Oncology Translational Network-Society for Immunotherapy of Cancer-American Association of Immunology Workshop on Combining Immunotherapy with Radiotherapy was convened to identify and prioritise opportunities and challenges for radiotherapy and immunotherapy combinations. Sessions examined the immune effects of radiation, barriers to anti-tumour immune response, previous clinical trial data, immunological and computational assessment of response, and next-generation radiotherapy-immunotherapy combinations. Panel recommendations included: developing and implementing patient selection and biomarker-guided approaches; applying mechanistic understanding to optimise delivery of radiotherapy and selection of immunotherapies; using rigorous preclinical models including companion animal studies; embracing data sharing and standardisation, advanced modelling, and multidisciplinary cross-institution collaboration; interrogating clinical data, including negative trials; and incorporating novel clinical endpoints and trial designs.

The induction of apoptosis in tumor cells is a common target for the development of anti-tumor therapies; however, these therapies still leave patients at increased risk of disease recurrence. For example, apoptotic tumor cells can promote tumor growth and immune evasion via the secretion of metabolites, apoptotic extracellular vesicles, and induction of pro-tumorigenic macrophages. This paradox of apoptosis induction and the pro-tumorigenic effects of tumor cell apoptosis has begged the question of whether apoptosis is a suitable cancer therapy, and led to further explorations into other immunogenic cell death-based approaches. However, these strategies still face multiple challenges, the most critical of which is the tumor microenvironment. Contrary to the promotion of immune tolerance mediated by apoptotic tumor cells, apoptotic bodies with enriched tumor-related antigens have demonstrated great immunogenic potential, as evidenced by their ability to initiate systemic T-cell immune responses. These characteristics indicate that apoptotic body-based therapies could be ideal "in situ" extra-tumoral tumor vaccine candidates for the treatment of cancers, and further address the current issues with apoptosis-based or immunotherapy treatments. Although not yet tested clinically, apoptotic body-based vaccines have the potential to better treatment strategies and patient outcomes in the future.

Due to the radiosensitivity and deep anatomical location of nasopharyngeal carcinoma (NPC), radiotherapy serves as the cornerstone of standardized treatment for this malignancy. Beyond its cytotoxic effects, radiotherapy can serve as an immunological adjuvant by inducing immunogenic cell death (ICD). Dendritic cells (DCs), as potent antigen-presenting cells, play a critical role in tumor immunotherapy, but their exact role in the ICD process of NPC remains unclear. The effects of high-dose radiation (≥2 Gy) on DCs and the type of immune response it elicits in NPC have not been fully elucidated.

An in vitro study was conducted to assess whether ICD of NPC 5-8F cells induced by high-dose radiation could regulate the immune response of DCs. Specifically, the maturation and antigen-presenting capacity of DCs were evaluated following co-culture with NPC cells exposed to high-dose radiation.

High-dose radiation was found to induce ICD in NPC 5-8F cells, as evidenced by increased pro-inflammatory factor levels and reduced anti-inflammatory factor levels in the cell culture supernatant. Co-culture with NPC cells exposed to high-dose radiation for 15 minutes significantly enhanced the expression of surface molecules on DCs, promoting their immune sensitization.

High-dose radiation-induced apoptosis of NPC 5-8F cells is a form of ICD, which plays an important role in regulating DC immune function. These findings provide insight into the immunomodulatory effects of radiotherapy in NPC and its potential to enhance tumor immunotherapy through DC activation.

Immunogenic cell death (ICD) enhances anti-tumor immunity by releasing tumor-associated antigens and activating the anti-tumor immune system response. However, its potential remains understudied in combination therapies. Here, we develop a mathematical model to quantify the role of ICD in optimizing the efficacy of combined radiotherapy (RT) and macrophage-based immunotherapy. Using preclinical murine data targeting the SIRP α -CD47 checkpoint, we show that RT alone induces minimal ICD, whereas disrupting the SIRP α -CD47 axis significantly enhances both phagocytosis and systemic immune activation. Our model predicts an optimal RT dose (6-8 Gy) for maximizing ICD, a dose-dependent abscopal effect, and a hierarchy of treatment efficacy, with SIRP α -knockout macrophages exhibiting the strongest tumoricidal activity. These findings provide a quantitative framework for designing more effective combination therapies, leveraging ICD to enhance immune checkpoint inhibition and radiotherapy synergy.

The presence of DNA in the cytosol triggers a protective response from the innate immune system. Cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) is an essential cytosolic DNA sensor that triggers a potent innate immune response. As a result of this signaling cascade reaction, type I interferon and other immune mediators activate an immune response. The cGAS-STING pathway has great anticancer immunity-boosting potential since it produces type I interferons. The detection of double-stranded DNA (dsDNA) in response to various stimuli initiates a protective host's cGAS-STING signals. So, it is clear that a substantial relationship is expected between cancer biotherapy and the functioning of the cGAS-STING pathway. Several STING agonists with promising outcomes have been created for preclinical cancer therapy research. Notably, immunotherapy has dramatically extended patient survival and radically altered the course of lung cancer treatment, particularly in more advanced instances. However, this method is still ineffective for a large number of lung cancer patients. cGAS-STING can overcome resistance and boost anticancer immunity by stimulating the activity of many pro-inflammatory mediators, augmenting dendritic cell cross-presentation, and initiating a tumor-specific CD8+ T cell response. This review aims to present the most recent results on the functionality of the cGAS-STING pathway in cancer progression and its potential as an immunotherapy target, with a focus on lung cancer.

Immunogenic cell death (ICD) of tumor cells, which is characterized by releasing immunostimulatory "find me" and "eat me" signals, expressing proinflammatory cytokines and providing personalized and broad-spectrum tumor antigens draws increasing attention in developing a tumor vaccine. In this study, we aimed to investigate whether the influenza virus (IAV) is efficient enough to induce ICD in tumor cells and an extra modification of IAV components such as hemeagglutinin (HA) will be helpful for the ICD-induced cells to elicit robust antitumor effects; in addition, to evaluate whether the membrane-engineering polylactic coglycolic acid nanoparticles (PLGA NPs) simulating ICD immune stimulation mechanisms hold the potential to be a promising vaccine candidate, a mouse melanoma cell line (B16-F10 cell) was infected with IAV rescued by the reverse genetic system, and the prepared cells and membrane-modified PLGA NPs were used separately to immunize the melanoma-bearing mice. IAV-infected tumor cells exhibit dying status, releasing high mobility group box-1 (HMGB1) and adenosine triphosphate (ATP), and exposing calreticulin (CRT), IAV hemeagglutinin (HA), and tumor antigens like tyrosinase-related protein 2 (TRP2). IAV-induced ICD cells enhance biomass-derived carbon (BMDCs) migration, antigen uptake, cross-presentation, and maturation in vitro. Furthermore, immunization with IAV-induced ICD cells effectively suppressed tumor growth in melanoma-bearing mice. The isolated cell membrane inherited the immunological characteristics from the ICD cells and elicited robust antitumor immune responses through decorating PLGA NPs loading with a tumor-specific helper T-cell peptide and supplemented with ATP in a hydrogel system. This study indicated a promising strategy for developing cell-based and personalized tumor vaccines through fully taking advantage of the immune stimulation mechanisms of ICD occurrence in tumor cells, IAV modification, and nanoscale delivery.

In the process of radiotherapy for cancer patients, there is an extremely low probability phenomenon that the distal tumor/metastasis away from the irradiation field undergoes regression after localized radiation therapy, which is called the abscopal effect. Enhancing the incidence of this phenomenon possesses profound significance for the investigation of metastatic cancer treatment. Currently, the underlying mechanisms of the abscopal effect remain unclear. Radiation-induced immunogenic cell death is considered one of the potential mechanisms for the abscopal effect. From this perspective, we explored how physical parameters and biological factors influence this process. Differences between patients with respect to physical factors and intrinsic biological factors that activate the immune response (acquired factors) may affect the induction of the abscopal effect.

Consolidation with PD-1/PD-L1-based immune checkpoint blockade after concurrent platinum-based chemo-radiotherapy has become the new standard of care for advanced stage III unresectable non-small cell lung cancer (NSCLC) patients. In order to further improve therapy outcomes, innovative combinatorial treatment strategies aim to target additional immunosuppressive barriers in the tumor microenvironment such as the CD73/adenosine pathway. CD73 and adenosine are known as crucial endogenous regulators of lung homeostasis and inflammation, but also contribute to an immunosuppressive tumor microenvironment. Furthermore, the CD73/adenosine pathway can also limit the immune-activating effects of cytotoxic therapies by degrading the pro-inflammatory danger molecule ATP, which is released into the tumor microenvironment and normal lung tissue upon therapy-induced cell damage. Thus, while targeting CD73 may enhance the efficacy of radio-immunotherapies in cancer treatment by mitigating tumor immune escape and improving immune-mediated tumor killing, it also raises concerns about increased immune-related adverse events (irAEs) in the normal tissue. In fact, combined radio-immunotherapies bear an increased risk of irAEs in the lungs, and additional pharmacologic inhibition of CD73 may further enhance the risk of overwhelming or overlapping pulmonary toxicity and thereby limit therapy outcome. This review explores how therapeutic interventions targeting CD73/adenosine dynamics could enhance radiation-induced immune activation in combined radio-immunotherapies, whilst potentially driving irAEs in the lung. We specifically investigate the interactions between radiotherapy and the CD73/adenosine pathway in radiation pneumonitis. Additionally, we compare the incidence of (radiation) pneumonitis reported in relevant trials to determine if there is an increased risk of irAEs in the clinical setting. By understanding these dynamics, we aim to inform future strategies for optimizing radio-immunotherapy regimens, ensuring effective cancer control while preserving pulmonary integrity and patient quality of life.

Despite enormous progress, advanced cancers are still one of the most serious medical problems in current society. Although various agents and therapeutic strategies with anticancer activity are known and used, they often fail to achieve satisfactory long-term patient outcomes and survival. Recently, immunotherapy has shown success in patients by harnessing important interactions between the immune system and cancer. However, many of these therapies lead to frequent side effects when administered systemically, prompting treatment modifications or discontinuation or, in severe cases, fatalities. New therapeutic approaches like intratumoral immunotherapy, characterized by reduced side effects, cost, and systemic toxicity, offer promising prospects for future applications in clinical oncology. In the context of locally advanced or metastatic cancer, combining diverse immunotherapeutic and other treatment strategies targeting multiple cancer hallmarks appears crucial. Such combination therapies hold promise for improving patient outcomes and survival and for promoting a sustained systemic response. This review aims to provide a current overview of immunotherapeutic approaches, specifically focusing on the intratumoral administration of drugs in patients with locally advanced and metastatic cancers. It also explores the integration of intratumoral administration with other modalities to maximize therapeutic response. Additionally, the review summarizes recent advances in intratumoral immunotherapy and discusses novel therapeutic approaches, outlining future directions in the field.

Radiotherapy (RT) triggers an immune response that contributes to antitumor effects. Induction of IFNβ is a key event in this immunogenicity of RT. We have previously shown that TRIM33, a chromatin reader, restrains IFNβ expression in Toll-like receptor-activated myeloid cells. In this study, we explored whether deleting Trim33 in myeloid cells might improve the radio-induced immune response and subsequent efficiency of RT. We first established that Trim33-/- bone marrow-derived macrophages showed increased expression of IFNβ in response to direct irradiation, or to treatment with irradiated cancer cells, further supporting our hypothesis. We then tested the efficiency of a single-dose RT in three subcutaneous tumor models and one orthotopic tumor model. In all models, myeloid deletion of Trim33 led to a significantly improved response after RT, leading to a complete and durable response in most of the treated mice bearing orthotopic oral tumors. This effect required the involvement of the type I IFN pathway and the presence of CD8+ T lymphocytes but not NK cells. In addition, cured mice were capable of rejecting a secondary tumor challenge, demonstrating an in situ vaccination effect. We conclude that deleting Trim33 in myeloid cells improves RT efficiency, through a mechanism involving the type I IFN pathway and the immune response. Our work suggests that myeloid Trim33 is a host factor affecting the tumor response to RT, thus representing a new potential therapeutic target for modifying RT responses.

Recently, attention has increasingly centered on non-small-cell lung cancer (NSCLC) with immune checkpoint inhibitors application. Numerous clinical studies have underscored the potential of immunotherapy in treating resectable NSCLC, highlighting its role in improving patient outcomes. However, despite these promising results, there is ongoing debate regarding the efficacy of immunological combination therapy strategies, the prevalence of treatment-related side effects, the identification of predictive biomarkers, and various other challenges within the neoadjuvant context. Careful consideration is essential to maximize the benefits of immunotherapy for patients with resectable NSCLC. This article offers a detailed overview of recent advancements in neoadjuvant immunotherapy for resectable NSCLC. By examining these developments, we aim to provide new perspectives and valuable insights into the benefits and challenges of applying neoadjuvant immunotherapy in clinical settings.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a poor prognosis. Although the addition of immunotherapy to chemotherapy has modestly improved outcomes, most patients rapidly develop resistance. Resistance to immunotherapy can be broadly categorized into primary resistance and acquired resistance, as proposed by the Society for Immunotherapy of Cancer (SITC) consensus definition. Primary resistance occurs in the setting of failure to respond to immune checkpoint inhibitors (ICIs), while acquired resistance develops after initial response. The mechanisms of acquired and primary resistance to ICI are not well understood in SCLC, denoting an area of critical unmet need. Both intrinsic and extrinsic mechanisms play significant roles in immunotherapy resistance. Intrinsic mechanisms include defects in antigen presentation, mutations in key genes, reduced tumor immunogenicity, and epigenetic alterations. Extrinsic mechanisms involve the tumor microenvironment (TME), which is a complex interplay of both tumor- and immunosuppressive immune cells, vasculature, and microbiome. An understanding of these resistance mechanisms is crucial for developing novel therapeutic strategies to advance effective immunotherapy in patients with SCLC, a critical area of unmet need.

Head and neck cancer (HNC) represents a challenging oncological entity with significant morbidity and mortality rates. Despite advances in conventional therapies, including surgery, chemotherapy, and radiation therapy, the overall survival rates for advanced HNC remain suboptimal. In recent years, the emerging field of oncolytic virotherapy has gained attention as a promising therapeutic approach for various malignancies, including HNC. This review provides a comprehensive overview of the current understanding of oncolytic viruses (Ovs) in the context of HNC treatment, including their mechanisms of action, preclinical and clinical studies, challenges, and future directions. Future oncolytic virotherapy focuses on improving delivery and specificity through nanoparticle carriers and genetic modifications to enhance tumor targeting and immune response. Combining different OVs and integrating them with immunotherapies, such as checkpoint inhibitors, could overcome tumor resistance and improve outcomes. Personalized approaches and rigorous clinical trials are key to ensuring the safety and effectiveness of virotherapy in treating HNC.

Immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for resectable non-small cell lung cancer. Numerous trials have explored the use of ICIs, either as monotherapy or in combination with other therapies, in the neoadjuvant setting for stage I-III non-small cell lung cancer. Most trials have demonstrated neoadjuvant immunotherapy to be safe and to have remarkable efficacy, with a high pathological response rate and significantly improved event-free survival. This review summarizes the findings of Phase I-III clinical trials investigating various neoadjuvant regimens, including ICI monotherapy, ICI therapy combined with chemotherapy, ICI plus anti-angiogenic therapy, dual ICI therapy, and ICI therapy in combination with radiotherapy or chemoradiotherapy. We discuss the benefits and outcomes associated with each approach. Despite the results being promising, several unresolved issues remain, including identification of reliable biomarkers, the appropriate duration of therapy, the optimal treatment regimen for tumors with high programmed cell death ligand 1 (PD-L1) expression, the false-negative pathological complete response rate, and the role of digital pathology in assessing the response to treatment. Resistance to immunotherapy, in particular, remains a significant barrier to effective use of ICIs. Given the critical influence of the tumor microenvironment (TME) on the response to treatment, we examine the characteristics of the TME in both responsive and resistant tumors as well as the dynamic changes that occur in the TME in response to neoadjuvant immunotherapy. We also summarize the mechanisms underlying T cell responses following neoadjuvant immunotherapy and provide a perspective on strategies to enhance the understanding of tumor heterogeneity, therapy-driven TME remodeling, and overcoming resistance to therapy. Finally, we propose future directions for advancements in personalized neoadjuvant immunotherapy.

Nonsmall Cell Lung Cancer (NSCLC) treatment relies on first-line immunotherapy as single agent or combined with chemotherapy. Oligoprogression may be observed in this setting.

We performed a European multicentric retrospective study on patients treated with first-line immunotherapy, who presented with oligoprogressive disease, treated with a local ablative treatment.

A total of 61 patients were retrospectively included between 2018 and 2022. Twenty-four patients (39%) received immunotherapy as single agent, and 37 (61%) chemo-immunotherapy. First oligoprogression occurred more frequently in pre-existing metastatic sites (47% of patients). Median PFS1 (defined as time to first oligoprogression) was 11.5 months [IC95%: 10.0-12.3]. We observed that 37 patients (61%) progressed after first oligoprogression, and 20 (54%) from them presented second oligoprogression. Median OS for the whole cohort was 72.0 months [IC95%: 19.3-124.8], with positive correlation between OS and PFS1 (R=0.65, P < .0001). After loco-ablative treatment with radiotherapy, disease control rate was 89% with ablative radiotherapy: 88% with conventional radiotherapy, and 89% with stereotactic radiotherapy.

Patients with oligoprogression under/after immunotherapy have better prognosis with a high risk of subsequent oligoprogression.

Neoadjuvant immunotherapy with chemotherapy improves outcomes in patients with resectable non-small-cell lung cancer (NSCLC). Given its immunomodulating effect, we investigated whether stereotactic body radiotherapy (SBRT) enhances the effect of immunochemotherapy.

The SACTION01 study was a single-arm, open-label, phase 2 trial that recruited patients who were 18 years or older and had resectable stage IIA-IIIB NSCLC from the Sun Yat-sen University Cancer Center, Guangzhou, China. Eligible patients received SBRT (24 Gy in three fractions) to the primary tumour followed by two cycles of 200 mg intravenous PD-1 inhibitor, tislelizumab, plus platinum-based chemotherapy. Surgical resection was performed 4-6 weeks after neoadjuvant treatment. The primary endpoint was major pathological response (MPR), defined as no more than 10% residual viable tumour in the resected tumour. All analyses were conducted on an intention-to-treat basis, including all patients who were scheduled for neoadjuvant treatment. The trial was registered with ClinicalTrials.gov (NCT05319574) and is ongoing but closed to recruitment.

Between May 18, 2022, and June 20, 2023, 46 patients (42 men and four women) were enrolled and scheduled for neoadjuvant treatment. MPR was observed in 35 (76%, 95% CI 61-87) of 46 patients. The second cycle of immunochemotherapy was withheld in four (9%) patients due to pneumonia (n=2), colitis (n=1), and increased creatinine (n=1). Grade 3 or worse adverse events related to neoadjuvant treatment occurred in 12 (26%, 95% CI 14-41) patients. The most frequent treatment-related adverse event (TRAE) was alopecia (16 [35%] patients), and the most frequent grade 3 or worse TRAE was neutropenia (six [13%]). There was one treatment-related death, caused by neutropenia. No deaths within 90 days of surgery were reported.

Preoperative SBRT followed by immunochemotherapy is well tolerated, feasible, and leads to a clinically significant MPR rate. Future randomised trials are warranted to support these findings.

BeiGene.

The efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors in the treatment of advanced colorectal cancer is controversial. This meta-analysis aimed to evaluate the efficacy and safety of PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors for advanced colorectal cancer.

PubMed, Embase, the Cochrane Library, and Web of Science databases were systematically searched for relevant studies. Outcomes including median progression-free survival (mPFS), median overall survival (mOS), overall response rate (ORR), disease control rate (DCR), treatment-related adverse events (TRAEs) and ≥grade 3 TRAEs were extracted for further analysis. The risk of bias was assessed by subgroup analysis.

12 articles with 566 patients were identified and subjected to meta-analysis. With regard to survival analysis, the pooled mOS and mPFS were 6.66 months (95%CI 4.85-9.16) and 2.92 months (95%CI 2.23-3.83), respectively. In terms of tumor response, the pooled ORR and DCR were 21% (95%CI 6%-41%) and 49% (95%CI 27%-71%), respectively. The pooled AEs rate and ≥ grade 3 AEs rate were 94% (95%CI 86%-99%) and 44% (95%CI 30%-58%).

PD-1/PD-L1 inhibitors combined with CTLA-4 inhibitors have shown promising clinical responses in the treatment of colorectal cancer (CRC). Although the incidence of adverse reactions is high, they are generally tolerable.

https://inplasy.com/, identifier INPLASY202480030.

Classic Hodgkin lymphoma (HL) is rare disease, with an incidence of approximately 85,000 patients globally per year and a predilection for adolescents and young adults (ages 15-39). Since the introduction of combination chemotherapy in the 1960's and radiation dating back to the early 1900's, therapeutic options and by extension, clinical outcomes have improved dramatically with 5-year overall survival (OS) approaching 90% today. [1](#ref-0001) Advances in understanding HL biology have additionally facilitated development of targeted agents and immunotherapy which have further improved short and long-term outcomes. Despite continued improvements in up-front and salvage therapy, long-term survivors of HL experience several treatment-associated late toxicities, thus, along with efforts to improve therapeutic efficacy, efforts to reduce late effects remain a high-priority in the field.

Whether to perform local radiotherapy on metastatic bone for primary bone-only oligometastatic nasopharyngeal carcinoma (NPC) patients remains unclear. Therefore, we analyzed the treatment methods and their survival and developed a prognostic model to predict outcomes and guide personalized treatment.

We studied 308 primary bone-only oligometastatic NPC patients who were treated with either palliative chemotherapy (PCT) alone, PCT combined with locoregional radiotherapy (LRRT), or PCT, LRRT, and radiotherapy to metastatic bones (bRT). The primary endpoint was overall survival (OS). Cox regression was utilized to identify independent prognostic factors, leading to the construction of a nomogram model. Patients were stratified into two risk groups based on median prognostic scores, and treatment modalities were compared using log-rank test while employing the inverse probability of treatment weighting (IPTW) to balance baseline characteristics and adjust for sample size differences between risk groups.

The best OS was observed in the group treated with PCT, LRRT, and bRT (HR = 0.60, 95% CI: 0.45-0.81, p = 0.002). Multivariable analysis revealed that age, N stage, pre-treatment levels of LDH, and EBV DNA were independent prognostic factors for OS. In total, 155 patients were in low-risk group while 153 were in high-risk group. Before and after IPTW, the high-risk group benefited from the PCT, LRRT, and bRT regimen (adjusted HR = 0.53, 95% CI: 0.42-0.67, p < 0.001; unadjusted HR = 0.59, 95% CI: 0.42-0.83, p = 0.007), while the low-risk group did not (adjusted HR = 0.79, 95% CI: 0.56-1.11, p = 0.345; unadjusted HR = 0.65, 95% CI: 0.37-1.14, p = 0.309).

Best outcomes of the whole cohort were seen with PCT + LRRT + bRT. Our study identified age, N stage, pre-treatment LDH levels, and EBV DNA levels as independent prognostic factors for OS. The high-risk group demonstrated a longer OS when treated with PCT + LRRT + bRT, whereas the low-risk group did not benefit from the combinatorial treatment.

To prospectively investigate levels of circulating cytokines, changes in frequencies of various immune cell subsets and expression of proliferation and checkpoint molecules on T cells in the peripheral blood after yttrium-90 radioembolization (TARE) of colorectal cancer liver metastases (CLM).

We prospectively collected, isolated, and froze peripheral blood mononuclear cells (PBMC) and plasma samples from 15 patients immediately before, immediately after, 3 and 6 weeks post-TARE of CLM. Plasma samples were assessed for various cytokines using a multiplex immunoassay platform. PBMC samples were analyzed in a monocyte/dendritic cell (DC)/B cell flow panel and a T cell activation/exhaustion flow phenotyping panel. We compared the levels at the respective time points using Wilcoxon signed rank test.

IFN-g significantly decreased immediately after (mean 1.62 vs. 3.02 at baseline, p = 0.04) and increased at 6 weeks compared to the immediately post-TARE nadir (mean 9.42 vs. 1.62, p = 0.04). IL-10 decreased at 3 weeks (mean 0.36 vs. 1.75, p = 0.025) post-TARE compared to baseline. Increased CD3+T cells (mean 78.24 vs. 60.8, p = 0.002) and decreased CTLA-4+CD4+T cells (mean 2.58 vs. 4.41, p = 0.033) were observed at 3 weeks compared to baseline. Increased Ki-67+ proliferating CD8+T cells at 3 and 6 weeks (mean 7.28 and 9.06, respectively, vs. 3.93 at baseline, p = 0.02 and 0.03) were recorded.

A shift toward a favorable antitumoral cytokinic and immune cells response was observed after TARE. Significant changes were in specialized immune cells subsets playing important roles in the activation of the immune system. These results support trials combining TARE with immunotherapy for patients with CLM.