Safety of combined ablative radiotherapy and immune checkpoint inhibitors in three phase I trials.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is safe and effective for treatment of extracranial metastatic disease, but its safety when combined with immune checkpoint inhibitors (ICI) has not yet been comprehensively reported. Here we report adverse events (AEs) associated with combined SBRT and ICI using prospectively-collected data on patients in three trials investigating multi-site SBRT combined with ICI. METHODS: Patients were included from three prospective trials of ICI (pembrolizumab; nivolumab/urelumab or nivolumab/cabiralizumab; nivolumab/ipilimumab) with SBRT to 1-4 sites. AEs were recorded prospectively using the CTCAE v4.0. Survival was analyzed using Kaplan-Meier method with a 90-day landmark. Association of patient characteristics with cumulative incidence of AEs was assessed using Fine-Gray regression. RESULTS: 213 patients were included, with a median follow-up of 10 months. Over the follow-up period, 50 % and 27 % of patients experienced at least one grade ≥ 2 or grade ≥ 3 AE, respectively. Cumulative incidences of grade ≥ 2 and grade ≥ 3 AEs at 6 months were 47 % and 23 %, respectively. Three grade 5 AEs rated "possibly" related to treatment occurred outside the 90-day dose-limiting toxicity window. Landmarked survival analysis of patients with or without grade ≥ 3 AEs showed no significant difference in progression-free or overall survival. Dual-agent ICI was significantly associated with grade ≥ 3 AE. CONCLUSION: This analysis features the largest prospectively evaluated cohort of patients treated with combination ablative SBRT and ICI to date and provides context for future trial design. We conclude that multi-site SBRT and ICI can be safely co-administered when SBRT is delivered with prioritization of normal tissue constraints.

Neighboring Effect-Initiated Supramolecular Nanocomplex with Sequential Infiltration as Irreversible Apoptosis Inducer for Synergetic Chemo-Immunotherapy.

Chemotherapy-based combination regimens are recommended as first-line treatment for colorectal cancer. However, multidrug resistance (MDR) and limited drug infiltration in tumor microenvironment remain critical challenges. Herein, a pH/redox dual activated supramolecular DAS@CD-OxPt (IV) nanoparticles (NPs) via host-guest molecular recognition to achieve relay drugs delivery of active oxaliplatin (OxPt (IV)) and Src inhibitor dasatinib (DAS) between tumor cells is developed. DAS@CD-OxPt (IV) NPs exhibit prolonged circulation in the blood and intra-tumoral retention. Triggered by the endo/lysosome (pH 5.0), flexible DAS@CD-OxPt (IV) NPs exhibited proton-driven in situ assembly to form nanofiber in tumor cells. Dual chemotherapeutic agents released from DAS@CD-OxPt (IV) NPs synergistically cause irreversible DNA damage by blocking p53-mediated DNA repair. Supramolecular nanofibers can further serve as the "ammunition depot" to continuously release drugs from dying cells and transport them into neighboring tumor cells, leading to domino-like cell death and enhanced immunogenicity. Furthermore, DAS@CD-OxPt (IV) NPs combined with immune checkpoint blockade (ICB) therapy strikingly suppress CT26 tumor growth and pulmonary metastasis.

Targeting the MHC-I endosomal-lysosomal trafficking pathway in cancer: From mechanism to immunotherapy.

Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8+ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.

IFNγ-Induced Bcl3, PD-L1 and IL-8 Signaling in Ovarian Cancer: Mechanisms and Clinical Significance.

IFNγ, a pleiotropic cytokine produced not only by activated lymphocytes but also in response to cancer immunotherapies, has both antitumor and tumor-promoting functions. In ovarian cancer (OC) cells, the tumor-promoting functions of IFNγ are mediated by IFNγ-induced expression of Bcl3, PD-L1 and IL-8/CXCL8, which have long been known to have critical cellular functions as a proto-oncogene, an immune checkpoint ligand and a chemoattractant, respectively. However, overwhelming evidence has demonstrated that these three genes have tumor-promoting roles far beyond their originally identified functions. These tumor-promoting mechanisms include increased cancer cell proliferation, invasion, angiogenesis, metastasis, resistance to chemotherapy and immune escape. Recent studies have shown that IFNγ-induced Bcl3, PD-L1 and IL-8 expression is regulated by the same JAK1/STAT1 signaling pathway: IFNγ induces the expression of Bcl3, which then promotes the expression of PD-L1 and IL-8 in OC cells, resulting in their increased proliferation and migration. In this review, we summarize the recent findings on how IFNγ affects the tumor microenvironment and promotes tumor progression, with a special focus on ovarian cancer and on Bcl3, PD-L1 and IL-8/CXCL8 signaling. We also discuss promising novel combinatorial strategies in clinical trials targeting Bcl3, PD-L1 and IL-8 to increase the effectiveness of cancer immunotherapies.

Anlotinib potentiates anti-PD1 immunotherapy via transferrin receptor-dependent CD8+ T-cell infiltration in hepatocellular carcinoma.

BACKGROUND: The therapeutic potential of immune checkpoint blockade (ICB) extends across various cancers; however, its effectiveness in treating hepatocellular carcinoma (HCC) is frequently curtailed by both inherent and developed resistance. OBJECTIVE: This research explored the effectiveness of integrating anlotinib (a broad-spectrum tyrosine kinase inhibitor) with programmed death-1 (PD-1) blockade and offers mechanistic insights into more effective strategies for treating HCC. METHODS: Using patient-derived organotypic tissue spheroids and orthotopic HCC mouse models, we assessed the effectiveness of anlotinib combined with PD-1 blockade. The impact on the tumour immune microenvironment and underlying mechanisms were assessed using time-of-flight mass cytometry, RNA sequencing, and proteomics across cell lines, mouse models, and HCC patient samples. RESULTS: The combination of anlotinib with an anti-PD-1 antibody enhanced the immune response against HCC in preclinical models. Anlotinib remarkably suppressed the expression of transferrin receptor (TFRC) via the VEGFR2/AKT/HIF-1α signaling axis. CD8+ T-cell infiltration into the tumour microenvironment correlated with low expression of TFRC. Anlotinib additionally increased the levels of the chemokine CXCL14, crucial for attracting CD8+ T cells. CXCL14 emerged as a downstream effector of TFRC, exhibiting elevated expression following the silencing of TFRC. Importantly, low TFRC expression was also associated with a better prognosis, enhanced sensitivity to combination therapy, and a favourable response to anti-PD-1 therapy in patients with HCC. CONCLUSIONS: Our findings highlight anlotinib's potential to augment the efficacy of anti-PD-1 immunotherapy in HCC by targeting TFRC and enhancing CXCL14-mediated CD8+ T-cell infiltration. This study contributes to developing novel therapeutic strategies for HCC, emphasizing the role of precision medicine in oncology. HIGHLIGHTS: Synergistic effects of anlotinib and anti-PD-1 immunotherapy demonstrated in HCC preclinical models. Anlotinib inhibits TFRC expression via the VEGFR2/AKT/HIF-1α pathway. CXCL14 upregulation via TFRC suppression boosts CD8+ T-cell recruitment. TFRC emerges as a potential biomarker for evaluating prognosis and predicting response to anti-PD-1-based therapies in advanced HCC patients.

Comparative study of immune response to local tumor destruction modalities in a murine breast cancer model.

Introduction: Immunotherapy is revolutionizing the management of multiple cancer types. However, only a subset of patients responds to immunotherapy. One mechanism of resistance is the absence of immune infiltrates within the tumor. In situ vaccine with local means of tumor destruction that can induce immunogenic cell death have been shown to enhance tumor T cell infiltration and increase efficacy of immune checkpoint blockade. Methods: Here, we compare three different forms of localize tumor destruction therapies: radiation therapy (RT), vascular targeted photodynamic therapy (VTP) and cryoablation (Cryo), which are known to induce immunogenic cell death, with their ability to induce local and systemic immune responses in a mouse 4T1 breast cancer model. The effects of combining RT, VTP, Cryo with anti-PD1 was also assessed. Results: We observed that RT, VTP and Cryo significantly delayed tumor growth and extended overall survival. In addition, they also induced regression of non-treated distant tumors in a bilateral model suggesting a systemic immune response. Flow cytometry showed that VTP and Cryo are associated with a reduction in CD11b+ myeloid cells (granulocytes, monocytes, and macrophages) in tumor and periphery. An increase in CD8+ T cell infiltration into tumors was observed only in the RT group. VTP and Cryo were associated with an increase in CD4+ and CD8+ cells in the periphery. Conclusion: These data suggest that cell death induced by VTP and Cryo elicit similar immune responses that differ from local RT.

Multifunctional Biomimetic Nanocarriers for Dual-Targeted Immuno-Gene Therapy Against Hepatocellular Carcinoma.

Growing evidences have proved that tumors evade recognition and attack by the immune system through immune escape mechanisms, and PDL1/Pbrm1 genes have a strong correlation with poor response or resistance to immune checkpoint blockade (ICB) therapy. Herein, a multifunctional biomimetic nanocarrier (siRNA-CaP@PD1-NVs) is developed, which can not only enhance the cytotoxic activity of immune cells by blocking PD1/PDL1 axis, but also reduce tumor immune escape via Pbrm1/PDL1 gene silencing, leading to a significant improvement in tumor immunosuppressive microenvironment. Consequently, the nanocarrier promotes DC cell maturation, enhances the infiltration and activity of CD8+ T cells, and forms long-term immune memory, which can effectively inhibit tumor growth or even eliminate tumors, and prevent tumor recurrence and metastasis. Overall, this study presents a powerful strategy for co-delivery of siRNA drugs, immune adjuvant, and immune checkpoint inhibitors, and holds great promise for improving the effectiveness and safety of current immunotherapy regimens.

Single-cell transcriptome dissecting the microenvironment remodeled by PD1 blockade combined with photodynamic therapy in a mouse model of oral carcinogenesis.

Oral squamous cell carcinoma (OSCC) stands as a predominant and perilous malignant neoplasm globally, with the majority of cases originating from oral potential malignant disorders (OPMDs). Despite this, effective strategies to impede the progression of OPMDs to OSCC remain elusive. In this study, we established mouse models of oral carcinogenesis via 4-nitroquinoline 1-oxide induction, mirroring the sequential transformation from normal oral mucosa to OPMDs, culminating in OSCC development. By intervening during the OPMDs stage, we observed that combining PD1 blockade with photodynamic therapy (PDT) significantly mitigated oral carcinogenesis progression. Single-cell transcriptomic sequencing unveiled microenvironmental dysregulation occurring predominantly from OPMDs to OSCC stages, fostering a tumor-promoting milieu characterized by increased Treg proportion, heightened S100A8 expression, and decreased Fib_Igfbp5 (a specific fibroblast subtype) proportion, among others. Notably, intervening with PD1 blockade and PDT during the OPMDs stage hindered the formation of the tumor-promoting microenvironment, resulting in decreased Treg proportion, reduced S100A8 expression, and increased Fib_Igfbp5 proportion. Moreover, combination therapy elicited a more robust treatment-associated immune response compared with monotherapy. In essence, our findings present a novel strategy for curtailing the progression of oral carcinogenesis.

STING-Activating Small Molecular Therapeutics for Cancer Immunotherapy.

Immuno-oncology has become a revolutionary strategy for cancer treatment. Therapeutic interventions based on adaptive immunity through immune checkpoint therapy or chimeric antigen receptor T cells have received clinical approval for monotherapy and combination treatment use in various cancers. Although these treatments have achieved clinical successes, only a minority of cancer patients show a response, highlighting the urgent need to discover new therapeutic molecules that could be exploited to improve clinical outcomes and pave the way for the next generation of immunotherapy. Given the critical role of the innate immune system against infection and cancer, substantial efforts have been dedicated to developing novel anticancer therapeutics that target these pathways. Targeting the stimulator of interferon genes (STING) pathway is a powerful strategy to generate durable antitumor response, and activation of the adaptor protein STING induces the initiation of transcriptional cascades, thereby producing type I interferons, pro-inflammatory cytokines and chemokines. Various STING agonists, including natural or synthetic cyclic dinucleotides (CDNs) have been developed as anticancer therapeutics. However, since most CDNs are confined to intratumoral administration, there has been a great interest in developing non-nucleotide agonists for systemic treatment. Here we review the current development of STING-activating therapeutics in both preclinical or clinical stages.

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

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

Evaluating [225Ac]Ac-FAPI-46 for the treatment of soft-tissue sarcoma in mice.

PURPOSE: Fibroblast Activation Protein (FAP) is an emerging theranostic target that is highly expressed on cancer-associated fibroblasts and on certain tumor cells including sarcoma. We investigated the anti-tumor efficacy of [225Ac]Ac-FAPI-46 as monotherapy or in combination with immune checkpoint blockade (ICB) in immunocompetent murine models of sarcoma sensitive or resistant to ICB. METHODS: [68Ga]Ga- and [225Ac]Ac-FAPI-46 were tested in subcutaneous FAP+ FSA fibrosarcoma bearing C3H/Sed/Kam mice. The efficacy of up to three cycles of 60 kBq [225Ac]Ac-FAPI-46 was evaluated as monotherapy and in combination with an anti-PD-1 antibody. Efficacy of [225Ac]Ac-FAPI-46 and/or ICB was further compared in FAP-overexpressing FSA (FSA-F) tumors that were sensitive to ICB or rendered ICB-resistant by tumor-induction in the presence of Abatacept. RESULTS: [225Ac]Ac-FAPI-46 was well tolerated up to 3 × 60 kBq but had minimal effect on FSA tumor growth. The combination of three cycles [225Ac]Ac-FAPI-46 and ICB resulted in growth delay in 55% of mice (6/11) and partial tumor regression in 18% (2/11) of mice. In FSA-F tumors with FAP overexpression, both [225Ac]Ac-FAPI-46 and ICB were effective without additional benefits from the combination. In locally immunosuppressed and ICB resistant FAP-F tumors, however, [225Ac]Ac-FAPI-46 restored responsiveness to ICB, resulting in significant tumor regression and tumor-free survival of 56% of mice in the combination group up to 60 days post treatment. CONCLUSION: [225Ac]Ac-FAPI-46 efficacy is correlated with tumoral FAP expression levels and can restore responsiveness to PD-1 ICB. These data illustrate that careful patient selection based on target expression and rationally designed combination therapies are critically important to maximize the therapeutic impact of FAP-targeting radioligands.

Immune surveillance of senescence: potential application to age-related diseases.

Several lines of evidence suggest that the age-dependent accumulation of senescent cells leads to chronic tissue microinflammation, which in turn contributes to age-related pathologies. In general, senescent cells can be eliminated by the host's innate and adaptive immune surveillance system, including macrophages, NK cells, and T cells. Impaired immune surveillance leads to the accumulation of senescent cells and accelerates the aging process. Recently, senescent cells, like cancer cells, have been shown to express certain types of immune checkpoint proteins as well as non-classical immune-tolerant MHC variants, leading to immune escape from surveillance systems. Thus, immune checkpoint blockade (ICB) may be a promising strategy to enhance immune surveillance of senescence, leading to the amelioration of some age-related diseases and tissue dysfunction.

Triterpenoids-templated self-assembly nanosystem for biomimetic delivery of CRISPR/Cas9 based on the synergy of TLR-2 and ICB to enhance HCC immunotherapy.

Combination immunotherapy has shown promising potential for enhancing the objective response rate compared to immune checkpoint blockade (ICB) monotherapy. However, combination therapy with multi-drugs is limited by the different properties of the agents and inconsistent synergistic targeted delivery. Herein, based on a universal triterpene template and the anticancer active agent ursolic acid (UA), a cytomembrane-coated biomimetic delivery nanoplatform (UR@M) prepared by the self-assembly of a PD-L1 targeted CRISPR/Cas9 system and UA was designed for hepatocellular carcinoma (HCC) treatment. UR@M showed enhanced tumor accumulation in vivo with homologous tumor targeting, and CRISPR in the nanosystem exhibited potent gene-editing efficiency of 76.53% in vitro and 62.42% in vivo with no off-target effects. UA activated the natural immune system through the TLR-2-MyD88-TRAF6 pathway, which synergistically enhanced the proliferation of natural killer cells and dendritic cells and realized excellent immune cytotoxic T cell infiltration by combining with the ICB of PD-L1. The strategy of work along both lines based on innate immune and adaptive immunity displayed a significant effect in tumor regression. Overall, the UA-templated strategy "killed three birds with one stone" by establishing a self-assembly nanosystem, inducing tumor cell death, and promoting synergistic immunostimulation for HCC treatment.

Robust anti-tumor immunity through the integration of targeted lipid nanoparticle-based mRNA nanovaccines with PD-1/PD-L1 blockade.

Tumor mRNA vaccines present a personalized approach in cancer immunotherapy, encoding distinct tumor antigens to evoke robust immune responses and offering the potential against emerging tumor variants. Despite this, the clinical advancement of tumor mRNA vaccines has been hampered by their limited delivery capacity and inefficient activation of antigen-presenting cells (APCs). Herein, we employed microfluidics technology to engineer mannose-modified lipid-based nanovaccines for specifically targeting APCs. The encapsulation process efficiently entrapped the cyclic guanosine monophosphate-adenosine monophosphate (cGAMP) agonist along with mRNA encoding antigens. The targeted nanovaccines (TNVs) exhibited a narrow particle size distribution, ensuring consistent and efficient delivery. These TNVs significantly enhanced gene expression of mRNA, facilitating antigen presentation and immune activation. When compared to non-targeted nanovaccines, TNVs outperformed in terms of antigen presentation and immune activation. Furthermore, the combination of anti-PD-L1 antibodies with TNVs elicited a synergistic anti-tumor effect. This was attributed to the anti-PD-L1 antibodies' ability to overcome the immune suppression of tumor cells. Our findings suggest that the combination treatment elicited the most robust anti-tumor immune activation and immune memory effect. These results indicate that integrating tumor mRNA vaccines with immune checkpoint inhibitors or other immunostimulatory agents may be crucial for enhancing the immune response.

Dual Adjuvant-Loaded Peptide Antigen Self-Assembly Potentiates Dendritic Cell-Mediated Tumor Immunotherapy.

Clinical translation of current cancer vaccine research has been hampered by limited antitumor immune responses due to inefficient antigen delivery and presentation, suboptimal DC and T cell activation. Biomaterial-based nanovaccine offers targeted antigen delivery, protection from degradation in vivo, and prolonged tumor therapeutic efficacy. This study introduces a lipid-coated deoxycholic acid-survivin nanoassembly (DA-L-DSA). Survivin, overexpressed in several cancer cells and involved in cancer cell growth and immune evasion, is selected as a tumor-associated antigen. An major histocompatibility complex class I binding epitope of survivin is engineered into the nanoassembly. R848, TLR 7/8 agonist, and SD-208, TGF-beta receptor1 kinase inhibitor, are coencapsulated into the nanoassembly as potent adjuvants to boost DC maturation and enhance antigen presentation. The DA-L-DSA effectively stimulates the maturation of dendritic cells, migrates into lymph nodes, and enhances T-cell activation and Th1 response. A substantial influx of cytotoxic T lymphocytes into primary tumors is observed in a murine melanoma model and demonstrates anti-metastatic effects in a spontaneous breast cancer metastasis model. Furthermore, DA-L-DSA exhibits a remarkable synergistic effect in the combination therapy with immune checkpoint inhibitors alleviating immunosuppressive tumor microenvironment. Taken together, these findings suggest DA-L-DSA as a promising immuno-therapeutic platform that could be applicable to diverse intractable cancers.

Systemic therapies and primary tumour downsizing in renal cell carcinoma: a real-world comparison of anti-angiogenic and immune checkpoint inhibition regimens.

PURPOSE: To investigate responses in the primary tumour to different systemic treatment regimens in patients with metastatic renal cell carcinoma (mRCC). METHODS: A single-centre retrospective analysis of treatment-naive mRCC patients without prior nephrectomy receiving VEGF tyrosine kinase inhibitors (VEGF only), immune checkpoint inhibitors (IO only), or combinations thereof (IO + VEGF). The primary outcome was the rate of partial response in the primary tumour (primary tumour PR, ≥ 30% diameter reduction). Secondary outcomes were time to best primary tumour diameter change, overall survival (OS) and progression-free survival (PFS) by Kaplan-Meier analysis. Predictors of survival outcomes were explored by Cox proportional hazards regression analysis. RESULTS: The rate of primary tumour PR was 14% for VEGF only (4/28 patients), 22% for IO only (5/23) and 50% for IO + VEGF (7/14), with median best primary tumour diameter change of - 8.0%, + 5.1%, and - 31.1% respectively, and median time to best primary tumour diameter change of 3.2, 3.0 and 6.9 months respectively. Median OS was significantly greater with IO + VEGF compared to VEGF only (HR 0.45, p = 0.04) and non-significantly greater compared to IO only (HR 0.46, p = 0.06). In multivariable analysis, primary tumour PR was the only response variable significantly associated with both OS (adjusted HR 0.32, p = 0.01) and PFS (adjusted HR 0.29, p < 0.01). CONCLUSION: mRCC patients without prior nephrectomy receiving first-line IO + VEGF regimens showed the greatest primary tumour responses, suggesting further prospective evaluation of this combination in the neoadjuvant and deferred cytoreductive nephrectomy settings.

Discovery and validation of a 10-gene predictive signature for response to adjuvant chemotherapy in stage II and III colon cancer.

Identifying patients with stage II and III colon cancer who will benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy is crucial for the advancement of personalized cancer therapy. We employ a semi-supervised machine learning approach to analyze a large dataset with 933 stage II and III colon cancer samples. Our analysis leverages gene regulatory networks to discover an 18-gene prognostic signature and to explore a 10-gene signature that potentially predicts chemotherapy benefits. The 10-gene signature demonstrates strong prognostic power and shows promising potential to predict chemotherapy benefits. We establish a robust clinical assay on the NanoString nCounter platform, validated in a retrospective formalin-fixed paraffin-embedded (FFPE) cohort, which represents an important step toward clinical application. Our study lays the groundwork for improving adjuvant chemotherapy and potentially expanding into immunotherapy decision-making in colon cancer. Future prospective studies are needed to validate and establish the clinical utility of the 10-gene signature in clinical settings.

Advances in Adjuvant and Neoadjuvant Therapy for Melanoma.

Melanoma remains one of the most common cancers diagnosed in the United States, yet there have been substantial advancements in the treatment of resectable disease. Adjuvant therapy with immune checkpoint blockade (ICB) and targeted therapy with BRAF/MEK inhibitors (BRAF/MEKi) have now become standard of care for resectable stage IIIB-IV melanoma. In this article, the authors discuss recent scientific developments pertinent to the treatment of resectable melanoma including ICB, targeted therapy with BRAF/MEKi, oncolytic viruses, tumor-infiltrating lymphocyte therapy, and cancer vaccines.

Regulation of ferroptosis by nanotechnology for enhanced cancer immunotherapy.

INTRODUCTION: This review explores the innovative intersection of ferroptosis, a form of iron-dependent cell death, with cancer immunotherapy. Traditional cancer treatments face limitations in efficacy and specificity. Ferroptosis as a new paradigm in cancer biology, targets metabolic peculiarities of cancer cells and may potentially overcome such limitations, enhancing immunotherapy. AREA COVERED: This review centers on the regulation of ferroptosis by nanotechnology to augment immunotherapy. It explores how nanoparticle-modulated ferroptotic cancer cells impact the TME and immune responses. The dual role of nanoparticles in modulating immune response through ferroptosis are also discussed. Additionally, it investigates how nanoparticles can be integrated with various immunotherapeutic strategies, to optimize ferroptosis induction and cancer treatment efficacy. The literature search was conducted using PubMed and Google Scholar, covering articles published up to March 2024. EXPERT OPINION: The manuscript underscores the promising yet intricate landscape of ferroptosis in immunotherapy. It emphasizes the need for a nuanced understanding of ferroptosis' impact on immune cells and the TME to develop more effective cancer treatments, highlighting the potential of nanoparticles in enhancing the efficacy of ferroptosis and immunotherapy. It calls for deeper exploration into the molecular mechanisms and clinical potential of ferroptosis to fully harness its therapeutic benefits in immunotherapy.