Immune checkpoint blockers have substantially improved prognosis of melanoma patients, nevertheless, resistance remains a significant problem. Here, intrinsic and extrinsic factors in the tumor microenvironment are discussed, including the expression of alternative immune checkpoints such as lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and mucin domain-containing protein 3 (TIM-3). While most studies focus on immune cell expression of these proteins, we investigated their melanoma cell intrinsic expression by immunohistochemistry in melanoma metastases of 60 patients treated with anti-programmed cell death protein 1 (PD-1) and/or anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapy, and correlated it with the expression of potential ligands, RNA sequencing data and clinical outcome. LAG-3 and TIM-3 were commonly expressed in melanoma cells. In the stage IV cohort, expression of LAG-3 was associated with M1 stage (p < 0.001) and previous exposure to immune checkpoint inhibitors (p = 0.029). Moreover, in the anti-PD-1 monotherapy treatment group patients with high LAG-3 expression by tumor cells tended to have a shorter progression-free survival (p = 0.088), whereas high expression of TIM-3 was associated with a significantly longer overall survival (p = 0.007). In conclusion, we provide a systematic analysis of melanoma cell intrinsic LAG-3 and TIM-3 expression, highlighting potential implications of their expression on patient survival.

Immune checkpoint inhibitors (ICIs) targeting programmed death ligand-1 (PD-L1) provide clinical benefits for various advanced malignancies. However, the predictive factors that determine sensitivity to ICIs have not been fully elucidated. We focused on tumor-derived CXCL10/11 as a pivotal factor that determines the response to PD-L1 blockade by regulating T cell accumulation and tumor angiogenesis. We previously reported that CXCL10/11 was upregulated by interferon (IFN)-γ in ICI-sensitive tumor cells but not in ICI-resistant cells, including mouse Lewis lung carcinoma (LLC). In the present study, gene silencing of tumor-derived CXCL10/11 induced resistance to PD-L1 blockade in AB1-HA mesothelioma cell-bearing mice. To identify the mechanisms underlying ICI resistance, we performed a microarray analysis to compare the IFN-γ-inducible genes between ICI-sensitive AB1-HA and ICI-resistant LLC in vitro. A pathway analysis based on microarray data indicated that hypoxia-inducible factor (HIF) 1A is the key signal that inhibits CXCL10/11 expression. We revealed that the HIF1A inhibitors echinomycin (EC) and YC-1 upregulated CXCL10/11 genes induced by IFN-γ in tumor cells in vitro. In addition, combination therapy with PD-L1 blockade and EC demonstrated synergistic antitumor effects in LLC-bearing mice. Combination therapy enhanced tumor infiltration of CD8 T cells and suppressed tumor angiogenesis. The present study suggests that HIF1A signaling in tumor cells dominates ICI resistance via the downregulation of tumor-derived CXCL10/11.

Bladder carcinoma (BC) is a common type of cancer. Approximately 20% of BC patients have non-muscle invasive bladder cancer (NMIBC). Despite adequate BCG treatment, recurrence occurs in approximately 40% of the patients. There is no adequate prognostic marker for recurrence in a group of patients. Forkhead box P3 (FOXP3) is a regulatory T cell marker that sometimes exhibits anti-tumoral effects and can be used as a tumor marker. T-cell immunoglobulin and mucin domain 3 (TIM-3) is an immune checkpoint inhibitor of T cells. Tertiary lymphoid structures (TLS) increase malignancy and inflammation in non-lymphoid organs. Therefore, we aimed to evaluate the prognostic value of FOXP3, TIM-3, and TLS in patients with NMIBC.

Patients with pathologically confirmed NMIBC were included in this study. Stromal and intraepithelial cells were evaluated separately using immunohistochemistry, and FOXP3, TIM-3, TLS, FOXP3/TLS, and TIM-3/TLS were calculated and noted. The cutoff value was determined using ROC analysis. Recurrence-free survival (RFS) and overall survival (OS) were evaluated using univariate and multivariate Cox proportional hazard analyses.

The study included ninety-six patients. FOXP3/TLS high group had a better RFS than FOXP3/TLS low group (P = 0.001; HR, 0.079; 95% CI, 0.019-0.337). This was also significant in the multivariate analysis (P = 0.018; HR, 0.125; 95% CI, 0.022-0.705). In the group receiving BCG, FOXP3/TLS, FOXP3-TLS, TIM-3-TLS and TIM-3/TLS elevation were lower in patients with relapse than in patients without relapse and were statistically significant. Combined TIM-3 and FOXP3 elevation was found to be good prognostic regardless of whether it was found in intraepithelial, stromal or TLS.

FOXP3/TLS elevation is a good prognostic and predictive marker in all non-muscle invasive bladder cancer cases and in the subgroup receiving BCG. Elevation of FOXP3-TLS, TIM-3-TLS, and TIM-3/TLS is associated with longer RFS in patients receiving BCG. Combined TIM-3 and FOXP3 elevation is indicative of a low recurrence rate in NMIBC.

Growth hormone (GH) is a pituitary-derived endocrine hormone required for normal postnatal growth and development. Hypo- or hypersecretion of endocrine GH results in 2 pathologic conditions, namely GH deficiency (GHD) and acromegaly. Additionally, GH is also produced in nonpituitary and tumoral tissues, where it acts rather as a cellular growth factor with an autocrine/paracrine mode of action. An increasingly persuasive and large body of evidence over the last 70 years concurs that GH action is implicit in escalating several cancer-associated events, locally and systemically. This pleiotropy of GH's effects is puzzling, but the association with cancer risk automatically raises a concern for patients with acromegaly and for individuals treated with GH. By careful assessment of the available knowledge on the fundamental concepts of cancer, suggestions from epidemiological and clinical studies, and the evidence from specific reports, in this review we aimed to help clarify the distinction of endocrine vs autocrine/paracrine GH in promoting cancer and to reconcile the discrepancies between experimental and clinical data. Along this discourse, we critically weigh the targetability of GH action in cancer-first by detailing the molecular mechanisms which posit GH as a critical node in tumor circuitry; and second, by enumerating the currently available therapeutic options targeting GH action. On the basis of our discussion, we infer that a targeted intervention on GH action in the appropriate patient population can benefit a sizable subset of current cancer prognoses.

Immune checkpoint blockade (ICB) inhibits tumor immune escape and has significantly advanced tumor therapy. However, ICB benefits only a minority of patients treated and may lead to many immune-related adverse events. Therefore, identifying factors that can predict treatment outcomes, enhance synergy with ICB, and mitigate immune-related adverse events is urgently needed.

Tertiary lymphoid structures (TLS) are ectopic lymphoid tissues that arise from the tumor periphery. They have been found to be associated with better prognosis and improved clinical outcomes after ICB therapy. TLS may help address the problems associated with ICB. The multiple mechanisms of action between TLS and ICB remain unknown. This paper described potential mechanisms of interaction between the two and explored their potential applications.

Bispecific antibodies (BsAb) combining simultaneous PD-L1 blockade and conditional costimulatory receptor activation have been developed to improve immune checkpoint therapy response. However, several PD-L1-based BsAbs have encountered clinical challenges, including insufficient activity or unexpected toxicity. In this study, we propose OX40 as a more suitable target partner for PD-L1-based BsAb design compared with ongoing clinical partners (CD27 and 4-1BB). We present a novel Fc-silenced tetravalent PD-L1/OX40 BsAb (EMB-09), which efficiently blocks PD-1/PD-L1 interactions and induces PD-L1-dependent OX40 activation, leading to enhanced T-cell activation. EMB-09 demonstrated improved antitumor activity compared with the anti-PD-L1 mAb. Significantly, EMB-09 activated effector memory T cells in the peripheral immune system and promoted the influx of stem-like CD8+ T cells into the tumor site, resulting in a more active phenotype of CD8+ tumor-infiltrating lymphocytes. In an ongoing first-in-human study in patients with advanced refractory solid tumors (NCT05263180), EMB-09 demonstrated a consistent pharmacodynamic response and early efficacy signals.

Therapeutic depletion of immunosuppressive regulatory T cells (Treg) may overcome resistance to cancer immunotherapies. RG6292 is an anti-CD25 antibody that preferentially depletes Tregs while preserving effector T-cell functions in preclinical models. The safety, pharmacokinetics, pharmacodynamics, and antitumor efficacy of selective Treg depletion by RG6292 administered as monotherapy or in combination with atezolizumab were evaluated in two phase I studies.

Adult patients with advanced solid tumors were administered intravenous RG6292, given every 3 weeks alone (study 1: NCT04158583, n = 76) or with 1,200 mg atezolizumab every 3 weeks (study 2: NCT04642365, n = 49). Both studies included dose escalation and expansion parts to determine the maximum tolerated dose and recommended phase II dose.

RG6292 was well tolerated. Pruritus and rash were the most frequent adverse events and were manageable with supportive treatment. Serum RG6292 levels increased dose proportionally, independent of the atezolizumab combination. RG6292 induced a sustained dose-dependent depletion of peripheral Tregs with no apparent effect on other immune cells. Evidence of intratumoral Treg reduction (≥50% vs. baseline) was observed at RG6292 doses of 35 to 100 mg. The maximum tolerated dose was 165 mg every 3 weeks, and the recommended phase II dose was proposed as 70 mg every 3 weeks. Objective responses were limited to three partial responses in patients receiving RG6292 combined with atezolizumab.

RG6292 induced a dose-dependent peripheral blood and measurable intratumoral Treg depletion in concordance with the proposed mode of action; however, clinical efficacy as a single agent or combined with atezolizumab was insufficient to warrant further exploration in this population.

RG6292 (vopikitug) targets CD25 (IL-2Rα) and mediates regulatory T-cell depletion while not interfering with IL-2 signaling. Peripheral and intratumoral Treg depletion was shown in two phase I studies. However, RG6292 alone or in combination with atezolizumab was insufficient to reverse and rescue from established resistance mechanisms in solid tumors.

Immune checkpoint therapy targeting the PD-1/PD-L1 axis has revolutionised the treatment of solid tumors. However, T cell exhaustion underpins resistance to current anti-PD-1 therapies, resulting in lower response rates in cancer patients. CD28 is a T cell costimulatory receptor that can influence the PD-1 signalling pathway (and vice versa). CD28 signalling has the potential to counter T cell exhaustion by serving as a potential complementary response to traditional anti-PD-1 therapies. Here we discuss the interplay between PD-1 and CD28 in T cell immunotherapy and additionally how CD28 transcriptionally modulates T cell exhaustion. We also consider clinical attempts at targeting CD28; the challenges faced by past attempts and recent promising developments.

The limitations of two-dimensional (2D) models in cancer research have hindered progress in fully understanding the complexities of drug resistance and therapeutic failures. However, three-dimensional (3D) models provide a more accurate representation of in vivo environments, capturing critical cellular interactions and dynamics that are essential in evaluating the efficacy and toxicity of tyrosine kinase inhibitors (TKIs). These advanced models enable researchers to explore drug resistance mechanisms with greater precision, optimizing treatment strategies and improving the predictive accuracy of clinical outcomes. By leveraging 3D models, it will be possible to deepen the current understanding of TKIs and drive forward innovations in cancer treatment. The present review discusses the limitations of 2D models and the transformative impact of 3D models on oncology research, highlighting their roles in addressing the challenges of 2D systems and advancing TKI studies.

Unleashing T cell function is critical for efficacious cancer immunotherapy. Here, we present an in vivo T cell activation strategy by silencing Casitas B-lineage lymphoma proto-oncogene b (Cbl-b), an intracellular checkpoint, to effectively combat solid tumors. The polymersomes are able to efficiently load and deliver siRNA against cblb to T cells both in vitro and in vivo, successfully silencing the cblb gene expression in primary T cells and enhancing the IL-2 receptor CD25 expression, which in turn enhances T cell function and prevents T cell exhaustion. In vitro and in vivo studies showed that siRNA against cblb caused an effective inhibition of tumor progression in subcutaneous B16-F10 and LLC models, in which a significant increase of effector T cells in peripheral blood mononuclear cells and an increase of effector T cells and a significant decrease of Treg cells in the tumor were clearly observed. This polymersome-mediated down-regulation of the cblb gene in T cells provides a promising approach for activating T cells and enhancing their anti-tumor capacity.

Despite remarkable clinical efficacy, little is known about the system-wide immunological alterations provoked by PD1 blockade. Dynamics of quantitative immune composition and functional repertoire during PD1 blockade could delineate cohort-specific patterns of treatment response and therapy-induced toxicity.

We longitudinally assessed therapy-induced effects on the immune system in fresh whole blood using flow cytometry-based cell quantifications, accompanied by analyses of effector properties of all major immune populations upon cell-type specific stimulations. 43 cancer patients undergoing PD1 blockade were recruited with assessments performed pre-treatment and before cycles 2/4/6, which resulted in the collection of more than 30,000 cytometric data values.

We observed no intrinsic immune pattern correlating with clinical outcome before PD1 blockade initiation, but cohort-specific immune alterations emerged during therapy. The most striking evolving changes in therapy responders were an increase in activated T and NK cell subsets, which showed high IFNγ and TNFα expression upon ex vivo stimulation. Patients affected by severe immune-related adverse events (s-irAE) presented with an analogously increased number of activated CD4 + and CD8 + T cells compared to patients with no/mild irAE, but lacked the functional divergences observed between responders versus non-responders. Instead, their monocytes showed discriminatory functional deficits with less IL10 production upon stimulation, which led to an abrogated inhibition of T cell proliferation in vitro and thus may account for the observed T cell expansion in patients with s-irAE.

Our holistic explorative approach allowed the delineation of clinically relevant cohorts by treatment-triggered immune changes, potentially enabling better patient stratification and further revealed new mechanistic insights into the pathogenesis of s-irAE.

Resistance to anti-PD-1 therapy in melanoma remains a major obstacle in achieving effective and durable treatment outcomes, highlighting the need to understand and address the underlying mechanisms. The first key factor is innate anti-PD-1 resistance signature (IPRES), an expression of a group of genes associated with tumor plasticity and immune evasion. IPRES promotes epithelial-to-mesenchymal transition (EMT), increasing melanoma cells' invasiveness and survival. Overexpressed AXL, TWIST2, and WNT5a induce phenotypic changes. The upregulation of pro-inflammatory cytokines frequently coincides with EMT-related changes, further promoting a resistant and aggressive tumor phenotype. Inflamed tumor microenvironment may also drive the expression of resistance. The complexity of immune resistance development suggests that combination therapies are necessary to overcome it. Furthermore, targeting epigenetic regulation and exploring novel approaches such as miR-146a modulation may provide new strategies to counter resistance in melanoma.

Bladder cancer (BLCA) is one of the ten most common cancers worldwide. However, the deregulation of PROS1 and its specific function in BLCA is not well understood. By combining proteomic and transcriptomic datasets, we discovered PROS1 expression was significantly reduced in BLCA tissues and revealed the clinical relevance of PROS1 with BLCA. Analysis of multiple BLCA datasets consistently showed the group with reduced PROS1 expression was linked to cancer-promoting pathways, more aggressive characteristics, and a greater chance of responding positively to immunotherapy. Next, various functional experiments were performed and the results revealed PROS1 overexpression inhibited the proliferation, cell cycle progression, migration, invasion, and angiogenesis of BLCA. In recovery trials, the AKT activator SC79 offered additional proof that PROS1 may influence BLCA cells via the AKT/GSK3β/β-catenin pathway. In conclusion, as an angiogenesis-related gene, PROS1 may play an inhibitory role in the biological functions of bladder cancer.

A minority subset of immunotherapy patients manifests hyperprogressive disease (HPD), with the disparity in melanoma subtypes yet to be reported. This study aimed to delineate the proportion and prognosis of HPD in patients receiving anti-PD-1 monotherapy and to identify patient with HPD clinical characteristics across melanoma subtypes to inform clinical decision making.

Utilizing 4 established HPD definitions, the incidence of HPD in patients with advanced melanoma on anti-PD-1 monotherapy was determined. The incidence rates and prognostic abilities of various HPD definitions were compared to elect the most effective one. This facilitated a comparative analysis of subtypes and clinical features between patients with HPD and traditional progression.

A total of 262 patients with advanced melanoma treated with anti-PD-1 monotherapy from 5 prospectively registered clinical trials were included in the study. The objective response rate (ORR) and disease control rate (DCR) was 21% and 58%, respectively, with 42% showcasing progression disease. The HPD incidences by 4 definitions were 13.2%, 16.8%, 10.8%, and 28.2%. All definitions effectively segregated HPD patients, with significantly poorer outcome than other progressive patients. The Delta TGR > 100 definition was the most indicative of a reduced overall survival, corroborated by the highest hazard ratio and statistical significance. The number of metastatic organs over 2 is a risk factor for HPD (OR = 4.18, P = .0103). Mucosal melanoma was the HPD prevalent subtype (OR = 3.13, P = .0489) in multivariable analysis, which is also indicated by RECIST criteria (P = .005).

A delta TGR exceeding 100 best identified HPD patients in the advanced melanoma population treated with anti-PD-1 monotherapy. Hyperprogression was notably prevalent in mucosal melanoma patients with multiple metastatic organs. Caution against HPD is warranted when applying anti-PD-1 monotherapy in mucosal subtype.

Immune-based combinations are the cornerstone of the first-line treatment of metastatic renal cell carcinoma patients, leading to outstanding outcomes. Nevertheless, primary resistance and disease progression is a critical clinical challenge. To properly address this issue, it is pivotal to understand the mechanisms of resistance to immunotherapy and tyrosine kinase inhibitors, that tumor eventually develop under treatment. In this review of the literature, we aim at exploring resistance mechanisms arising in patients treated with first-line immune-based combinations in order to understand the biological pattern that should be investigated to overcome them. In more detail, mechanisms of resistance to nivolumab and pembrolizumab are divided into intrinsic to cancer cells and extrinsic (stromal or immune cells). Regarding axitinib, the increased expression of Nuclear protein 1 (NUPR1) or decreased levels of insulin receptor (INSR) characterize resistant cells. The secretion of non-VEGF pro-angiogenic factors, such as PDGF-BB, IL-1β, MMP-9, Gro-α, IL-8, IL-6, and CCL-2, can lead to resistance to cabozantinib. The reactivation of pathways previously targeted by lenvatinib or the activation of alternative pathways, such as EGFR-PAK2-ERK pathway, underlie the development of resistance to lenvatinib. Exploring resistance mechanism that arise during first-line therapy can lead to the development of treatment strategy able to overcome them in order to improve duration of response and patients outcomes.

Glioblastoma (GBM), the most common and aggressive primary central nervous system (CNS) tumor in adults, continues to have a dismal prognosis. Across hundreds of clinical trials, few novel approaches have translated to clinical practice while survival has improved by only a few months over the past three decades. Randomized controlled trials of immune checkpoint inhibitors (ICIs), which have seen impressive success for advanced or metastatic extracranial solid tumors, have so far failed to demonstrate a clinical benefit for patients with GBM. This has been secondary to GBM heterogeneity, the unique immunosuppressive CNS microenvironment, immune-evasive strategies by cancer cells, and the rapid evolution of tumor on therapy. This review aims to summarize findings from major clinical trials of ICIs for GBM, review historic failures, and describe currently promising avenues of investigation. We explore the biological mechanisms driving ICI responses, focusing on the role of the tumor microenvironment, immune evasion, and molecular biomarkers. Beyond conventional monotherapy approaches targeting PD-1, PD-L1, CTLA-4, we describe emerging approaches for GBM, such as dual-agent ICIs, and combination of ICIs with oncolytic virotherapy, antigenic peptide vaccines, chimeric antigenic receptor (CAR) T-cell therapy, along with nanoparticle-based delivery systems to enhance ICI efficacy. We highlight potential strategies for improving patient selection and treatment personalization, along with real-time, longitudinal monitoring of therapeutic responses through advanced imaging and liquid biopsy techniques. Integrated radiomics, tissue, and plasma-based analyses, may potentially uncover immunotherapeutic response signatures, enabling early, adaptive therapeutic adjustments. By specifically targeting current therapeutic challenges, outcomes for GBM patients may potentially be improved.

Lymphoma accounts for 24% of all documented canine neoplasms and 85% of hematological malignancies, while multicentric lymphoma corresponds to 84% of all canine lymphomas. Canine lymphomas of B-cell origin account for 60% to 80% of lymphomas. Similar to humans, the histologic grade, architecture, as well as immunophenotype determination, are crucial. These lesions are the most prevalent spontaneous tumors in dogs and this species may be a valuable animal model for the study of human non-Hodgkin's lymphoma. Therefore, it is important to investigate and assess therapeutic responses and to seek predictive and prognostic factors in order to allow for the development of an individualized and more effective therapy that increases survival. This review aims to describe current knowledge on the diagnosis, treatment, and prognostic factors of canine multicentric lymphoma.

Bladder cancer is one of the most common malignancies of the urinary system and has always presented great challenges in treatment due to its intricate biological features and high recurrence rates. Although great developments were achieved in immunotherapy and targeted therapies within the last decade, therapeutic outcomes for a great number of patients remain unsatisfactory, particularly as to long-term efficacy. Review discusses the molecular mechanisms developed during the process of bladder cancer progression: genetic and epigenetic alterations, dynamics of the tumor microenvironment (TME), and dysregulation and abnormal activation of various signaling pathways-all contributing to therapeutic resistance. It is genetic mutation, especially in both low- and high-grade tumors, that, alongside epigenetic modifications, plays a considerable role in tumor aggressiveness and drug resistance. TME, comprising cancer-associated fibroblasts (CAFs), immunosuppressive cells, and different components of the extracellular matrix (ECM), orchestrates a setting that fosters tumor growth and immune evasion and confers resistance on any therapeutic regime that might be used. The review also provides an overview of PI3K/AKT and MAPK signaling pathways in the progression of bladder cancer and the development of targeted therapies against them. Further, it discusses the challenges and mechanisms of resistance to immunotherapy, including those involving immune checkpoint inhibitors. Other promising approaches include the development of new therapeutic strategies that target not only the signaling pathways but also immune checkpoints in combination therapies. This review aims to contribute to the elaboration of more effective and personalized treatment strategies by fully understanding the underlying mechanisms involved in bladder cancer.

Engineered probiotics are an emerging platform for in situ delivery of therapeutics to the gut. Herein, we developed an orally administered, yeast-based therapeutic delivery system to deliver next-generation immune checkpoint inhibitor (ICI) proteins directly to gastrointestinal tumors. We engineered Saccharomyces cerevisiae var. boulardii (Sb), a probiotic yeast with high genetic tractability and innate anticancer activity, to secrete "miniature" antibody variants that target programmed death ligand 1 (Sb_haPD-1). When tested in an ICI-refractory colorectal cancer (CRC) mouse model, Sb_haPD-1 significantly reduced intestinal tumor burden and resulted in significant shifts to the immune cell profile and microbiome composition. This oral therapeutic platform is modular and highly customizable, opening new avenues of targeted drug delivery that can be applied to treat a myriad of gastrointestinal malignancies.

The last decade has witnessed unprecedented succusses with the use of immune checkpoint inhibitors in treating cancer. Nevertheless, the proportion of patients who respond favorably to the treatment remained rather modest, partially due to treatment resistance. This has fueled a wave of research into potential mechanisms of resistance to immune checkpoint inhibitors which can be classified into primary resistance or acquired resistance after an initial response. In the current review, we summarize what is known so far about the mechanisms of resistance in terms of being tumor-intrinsic or tumor-extrinsic taking into account the multimodal crosstalk between the tumor, immune system compartment and other host-related factors.

The primary node molecules in the cell signaling network in cancer tissues are maladjusted and mutated in comparison to normal tissues, which promotes the occurrence and progression of cancer. Pancreatic cancer (PC) is a highly fatal cancer with increasing incidence and low five-year survival rates. Currently, there are several therapies that target cell signaling networks in PC. However, PC is a "cold tumor" with a unique immunosuppressive tumor microenvironment (poor effector T cell infiltration, low antigen specificity), and targeting a single gene or pathway is basically ineffective in clinical practice. Targeted matrix therapy, targeted metabolic therapy, targeted mutant gene therapy, immunosuppressive therapy, cancer vaccines, and other emerging therapies have shown great therapeutic potential, but results have been disappointing. Therefore, we summarize the identified and potential drug-resistant cell signaling networks aimed at overcoming barriers to existing PC therapies.

Rationale: Tumor cells possess sophisticated strategies to circumvent immune detection, including the modulation of endogenous immune checkpoints, particularly those within the B7 family. Elucidating the mechanisms that govern the induction of B7 family molecules is crucial for the advancement of immunotherapy. Lysine lactylation (Kla), a newly identified epigenetic modification, is suggested may play a role in reshaping the tumor microenvironment and facilitating immune evasion. Methods: We analyzed the glycolysis pathway's enrichment in patients with immune-evading tumors and assessed the impact of lactate treatment on the antitumor immunity of CD8+ T cells in the tumor microenvironment. We interrupted glycolysis using lactate dehydrogenase A (LDHA) knockdown and sodium oxamate, and evaluated its effects on CD8+ T cell cytotoxicity. Additionally, we investigated the correlation between B7-H3 expression and the glycolysis pathway, and explored the molecular mechanisms underlying lactate-induced B7-H3 expression. Results: Our findings revealed that the glycolysis pathway was highly enriched in immune-evading tumors. Lactate treatment inhibited the antitumor immunity of CD8+ T cells, whereas interruption of glycolysis via LDHA knockdown or treatment with sodium oxamate augmented the cytotoxicity of CD8+ T cells, effectively counteracting tumor immune evasion. B7-H3 expression was found to be closely linked with the glycolysis pathway. Mechanistically, lactate-upregulated H3K18la directly bound to the B7-H3 promoter in conjunction with the transcription factor Creb1 and its co-activator Ep300, leading to increased B7-H3 expression and contributing to tumor progression by compromising the proportion and cytotoxicity of tumor-infiltrating CD8+ T cells. In mouse tumor bearing models, inhibiting glycolysis and B7-H3 expression suppressed tumor cell growth, activated tumor-infiltrating CD8+ T cells, and demonstrated potent anti-tumor efficacy. Furthermore, this approach enhanced the efficacy of anti-PD-1 treatment. Conclusions: This study uncovers a novel mechanism by which lactate modulates the immune microenvironment through the glycolysis pathway and B7-H3 expression, providing new avenues for lactate metabolism-targeted tumor immunotherapy.

Background: Despite significant strides in anti-melanoma therapies, resistance and recurrence remain major challenges. A deeper understanding of the underlying biology of these challenges is necessary for developing more effective treatment paradigms. Methods: Melanoma single-cell data were retrieved from the Broad Single Cell Portal (SCP11). High-dimensional weighted gene co-expression network analysis (hdWGCNA), CellChat, and ligand-receptor relative crosstalk (RC) scoring were employed to evaluate intercellular and intracellular signaling. The prognostic value of key regulatory genes was assessed via Kaplan-Meier (KM) survival analysis using the 'SKCM-TCGA' dataset. Results: Twenty-seven (27) gene co-expression modules were identified via hdWGCNA. Notable findings include NRAS Q61L melanomas being enriched for modules involving C19orf10 and ARF4, while BRAF V600E melanomas were enriched for modules involving ALAS1 and MYO1B. Additionally, CellChat analysis highlighted several dominant signaling pathways, namely MHC-II, CD99, and Collagen-receptor signaling, with numerous significant ligand-receptor interactions from melanocytes, including CD99-CD99 communications with cancer-associated fibroblasts, endothelial cells, NK cells, and T-cells. KM analysis revealed that higher expression of SELL, BTLA, IL2RG, PDGFA, CLDN11, ITGB3, and SPN improved overall survival, while higher FGF5 expression correlated with worse survival. Protein-protein interaction network analysis further indicated significant interconnectivity among the identified prognostic genes. Conclusions: Overall, these insights underscore critical immune interactions and potential therapeutic targets to combat melanoma resistance, paving the way for more personalized and effective treatment strategies.

Cancer immunotherapy, including immune checkpoint inhibitors, chimeric antigen receptor T-cell therapy and bispecific antibodies, has led to major improvements in the treatment of a wide range of hematologic malignancies and solid tumors. However, age-mediated immune system modifications, known as immunosenescence, may preclude its efficacy in elderly patients. In this review, we assessed the efficacy of these different cancer immunotherapies in elderly patients compared to young patients to revisit the concept of immunosenescence from a therapeutic perspective.

While the emergence of immunotherapies has fundamentally altered the management of solid tumors, cancers exploit many complex biological mechanisms that result in resistance to these agents. These encompass a broad range of cellular activities - from modification of traditional paradigms of immunity via antigen presentation and immunoregulation to metabolic modifications and manipulation of the tumor microenvironment. Intervening on these intricate processes may provide clinical benefit in patients with solid tumors by overcoming resistance to immunotherapies, which is why it has become an area of tremendous research interest with practice-changing implications. This review details the major ways cancers avoid both natural immunity and immunotherapies through primary (innate) and secondary (acquired) mechanisms of resistance, and it considers available and emerging therapeutic approaches to overcoming immunotherapy resistance.

The discovery of immune checkpoints and the development of immune checkpoint inhibitors (ICI) have achieved a durable response in advanced-stage cancer patients. However, there is still a high proportion of patients who do not benefit from ICI therapy due to a lack of response when first treated (primary resistance) or detection of disease progression months after objective response is observed (acquired resistance). Here, we review the current FDA-approved ICI for the treatment of certain solid malignancies, evaluate the contrasting responses to checkpoint blockade in different cancer types, explore the known mechanisms associated with checkpoint blockade resistance (CBR), and assess current strategies in the field that seek to overcome these mechanisms. In order to improve current therapies and develop new ones, the immunotherapy field still has an unmet need in identifying other molecules that act as immune checkpoints, and uncovering other mechanisms that promote CBR.

Immunology-based therapies are emerging as an effective cancer treatment, using the body's immune system to target tumors. Immune checkpoints, which regulate immune responses to prevent tissue damage and autoimmunity, are often exploited by cancer cells to avoid destruction. The discovery of checkpoint proteins like PD-1/PD-L1 and CTLA-4 was pivotal in developing cancer immunotherapy. Immune checkpoint inhibitors (ICIs) have shown great success, with FDA-approved drugs like PD-1 inhibitors (Nivolumab, Pembrolizumab, Cemiplimab), PD-L1 inhibitors (Atezolizumab, Durvalumab, Avelumab), and CTLA-4 inhibitors (Ipilimumab, Tremelimumab), alongside LAG-3 inhibitor Relatlimab. Research continues on new checkpoints like TIM-3, VISTA, B7-H3, BTLA, and TIGIT. Biomarkers like PDL-1 expression, tumor mutation burden, interferon-γ presence, microbiome composition, and extracellular matrix characteristics play a crucial role in predicting responses to immunotherapy with checkpoint inhibitors. Despite their effectiveness, not all patients experience the same level of benefit, and organ-specific immune-related adverse events (irAEs) such as rash or itching, colitis, diarrhea, hyperthyroidism, and hypothyroidism may occur. Given the rapid advancements in this field and the variability in patient outcomes, there is an urgent need for a comprehensive review that consolidates the latest findings on immune checkpoint inhibitors, covering their clinical status, biomarkers, resistance mechanisms, strategies to overcome resistance, and associated adverse effects. This review aims to fill this gap by providing an analysis of the current clinical status of ICIs, emerging biomarkers, mechanisms of resistance, strategies to enhance therapeutic efficacy, and assessment of adverse effects. This review is crucial to furthering our understanding of ICIs and optimizing their application in cancer therapy.

Immune checkpoint inhibitors (ICI) have become integral to treatment of non-small cell lung cancer (NSCLC). However, reliable biomarkers predictive of immunotherapy efficacy are limited. Here, we introduce HistoTME, a novel weakly supervised deep learning approach to infer the tumor microenvironment (TME) composition directly from histopathology images of NSCLC patients. We show that HistoTME accurately predicts the expression of 30 distinct cell type-specific molecular signatures directly from whole slide images, achieving an average Pearson correlation of 0.5 with the ground truth on independent tumor cohorts. Furthermore, we find that HistoTME-predicted microenvironment signatures and their underlying interactions improve prognostication of lung cancer patients receiving immunotherapy, achieving an AUROC of 0.75 [95% CI: 0.61-0.88] for predicting treatment responses following first-line ICI treatment, utilizing an external clinical cohort of 652 patients. Collectively, HistoTME presents an effective approach for interrogating the TME and predicting ICI response, complementing PD-L1 expression, and bringing us closer to personalized immuno-oncology.

Localized cancer therapies such as radiotherapy, phototherapy, and chemotherapy are precise cancer treatment strategies aimed at minimizing systemic side effects. However, cancer metastasis remains the primary cause of mortality among cancer patients in clinical settings, and localized cancer treatments have limited efficacy against metastatic cancer. Therefore, researchers are exploring strategies that combine localized therapy with immunotherapy to activate robust anti-tumor immune responses, thereby eradicating metastatic cancer. Biomaterials, as novel materials, exhibit great potential in biomedical applications and have achieved great progress in clinic translation. This review introduces biomaterials and their applications in research focused on enhancing localized cancer treatment activated anti-tumor immunity. Additionally, the current challenges and future directions of biomaterials are also discussed, providing insights and references for related research.

Mutations in the NRF2-KEAP1 pathway are common in non-small cell lung cancer (NSCLC) and confer broad-spectrum therapeutic resistance, leading to poor outcomes. Currently, there is no means to non-invasively identify NRF2 activation in living subjects. Here, we show that positron emission tomography imaging with the system xc- radiotracer, [18F]FSPG, provides a sensitive and specific marker of NRF2 activation in orthotopic, patient-derived, and genetically engineered mouse models of NSCLC. We found a NRF2-related gene expression signature in a large cohort of NSCLC patients, suggesting an opportunity to preselect patients prior to [18F]FSPG imaging. Furthermore, we reveal that system xc- is a metabolic vulnerability that can be therapeutically targeted with an antibody-drug conjugate for sustained tumour growth suppression. Overall, our results establish [18F]FSPG as a predictive marker of therapy resistance in NSCLC and provide the basis for the clinical evaluation of both imaging and therapeutic agents that target this important antioxidant pathway.

Using artificial intelligence (AI) to enhance chimeric antigen receptor (CAR)-based therapies' design, production, and delivery is a novel and promising approach. This review provides an overview of the current applications and challenges of AI for CAR-based therapies and suggests some directions for future research and development. This paper examines some of the recent advances of AI for CAR-based therapies, for example, using deep learning (DL) to design CARs that target multiple antigens and avoid antigen escape; using natural language processing to extract relevant information from clinical reports and literature; using computer vision to analyze the morphology and phenotype of CAR cells; using reinforcement learning to optimize the dose and schedule of CAR infusion; and using AI to predict the efficacy and toxicity of CAR-based therapies. These applications demonstrate the potential of AI to improve the quality and efficiency of CAR-based therapies and to provide personalized and precise treatments for cancer patients. However, there are also some challenges and limitations of using AI for CAR-based therapies, for example, the lack of high-quality and standardized data; the need for validation and verification of AI models; the risk of bias and error in AI outputs; the ethical, legal, and social issues of using AI for health care; and the possible impact of AI on the human role and responsibility in cancer immunotherapy. It is important to establish a multidisciplinary collaboration among researchers, clinicians, regulators, and patients to address these challenges and to ensure the safe and responsible use of AI for CAR-based therapies.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy by enhancing the antitumor immune response. This case describes an 80-year-old male with synchronous multiple primary malignancies (MPMs), including lung metastatic hepatocellular carcinoma (HCC), and non-small cell lung carcinoma (NSCLC), and brain metastatic urothelial carcinoma, who was treated with dual ICI therapy.

The patient, with a history of diabetes, hypertension, dyslipidaemia, well-differentiated neuroendocrine duodenal tumors and micronodular exogenous cirrhosis (Child-Pugh class A), presented with a non-invasive bladder carcinoma (pT1N0M0) resected endoscopically in December 2022. Incidentally discovered hepatic and pulmonary tumors were confirmed as primary HCC and squamous cell carcinoma of the lung (cT1bN0M0, PD-L1 expression 100%), respectively. Due to the rapid progression of pulmonary metastases secondary to HCC, dual ICI therapy (durvalumab and tremelimumab) was initiated, resulting in a partial response (>30%) according to RECISTv1.1 criteria in pulmonary and hepatic lesions. After one year of ICI therapy, cerebellar syndrome due to secondary brain lesions emerged, which was confirmed as urothelial metastases. Surgical resection of the symptomatic cerebral metastases was completed with cerebral radiotherapy, and ICIs were continued. The patient is still receiving dual ICIs.

This case highlights the crucial role of ICIs in treating MPMs. The patient's favourable response suggests the importance of PD-L1 expression as a predictive biomarker.

This rare case showed dual ICI therapy efficacy across multiple malignancies. Effective multidisciplinary collaboration and biomarker evaluation are crucial for managing such complex cases.

The loss of major histocompatibility complex class I (MHC-I) molecules has been proposed as a mechanism by which cancer cells evade tumor-specific T cells in immune checkpoint inhibitor (ICI)-refractory patients. Nevertheless, the mechanism by which cancer cells downregulate MHC-I is poorly understood. We report here that membrane-associated RING-CH-type finger 8 (MARCHF8), upregulated by human papillomavirus (HPV), ubiquitinates and degrades MHC-I proteins in HPV-positive head and neck cancer (HPV+ HNC). MARCHF8 knockdown restores MHC-I levels on HPV+ HNC cells. We further reveal that Marchf8 knockout significantly suppresses tumor growth and increases the infiltration of natural killer (NK) and T cells in the tumor microenvironment (TME). Furthermore, Marchf8 knockout markedly increases crosstalk between the cytotoxic NK cells and CD8 + T cells with macrophages and enhances the tumor cell-killing activity of CD8 + T cells. CD8 + T cell depletion in mice abrogates Marchf8 knockout-driven tumor suppression and T cell infiltration. Interestingly, Marchf8 knockout, in combination with anti-PD-1 treatment, synergistically suppresses tumor growth in mice bearing ICI-refractory tumors. Taken together, our finding suggests that MARCHF8 could be a promising target for novel immunotherapy for HPV+ HNC patients.

Targeting MARCHF8 restores MHC-I proteins, induces antitumor CD8 + T cell activity, and suppresses the growth of ICI-refractory tumors.

An accumulating number of studies suggest the potential of circulating cell-free microbial DNA (cfmDNA) as a non-invasive biomarker in various diseases, including cancers. However, its value in the prediction or prognosis of clinical outcomes of immune checkpoint inhibitors (ICIs) is poorly explored. The circulating cfmDNA pool may also reflect the translocation of various microbial ligands to the circulatory system and may be associated with the increased release of soluble CD14 (sCD14) by myeloid cells. In the present study, blood samples were collected from advanced melanoma patients (n = 66) before and during the anti-PD-1 therapy (approximately 3 and 12 months after the start). Then, V3-V4 16S rRNA gene sequencing was performed to analyze the circulating cfmDNA extracted from plasma samples. Moreover, the concentration of plasma sCD14 was measured using ELISA. As a result, the differences in the circulating cfmDNA profiles were found between patients with favorable and unfavorable clinical outcomes of the anti-PD-1 and baseline signatures correlated with progression-free survival and overall survival. Moreover, there was a higher concentration of plasma sCD14 in patients with unfavorable clinical outcomes. High baseline sCD14 level and its increase during the therapy prognosticated worse survival outcomes. Taken together, this preliminary study indicates the potential of circulating cfmDNA signatures and plasma sCD14 levels as biomarkers of clinical outcomes of ICIs.

Glioblastoma (GBM) is an aggressive and lethal type of brain tumor in human adults. The standard of care offers minimal clinical benefit, and most GBM patients experience tumor recurrence after treatment. In recent years, significant advancements have been made in the development of novel immunotherapies or other therapeutic strategies that can overcome immunotherapy resistance in many advanced cancers. However, the benefit of immune-based treatments in GBM is limited because of the unique brain immune profiles, GBM cell heterogeneity, and immunosuppressive tumor microenvironment. In this review, we present a detailed overview of current immunotherapeutic strategies and discuss the challenges and potential molecular mechanisms underlying immunotherapy resistance in GBM. Furthermore, we provide an in-depth discussion regarding the strategies that can overcome immunotherapy resistance in GBM, which will likely require combination therapies.

Anticancer systemic therapy comprises a complex and growing group of drugs. Some of the new agents with novel mechanisms of action that have appeared are difficult to fit in the groups of classical chemotherapy, hormones, tyrosine-kinase inhibitors, and monoclonal antibodies. We propose a classification based on two levels of information: the site of action and the mechanism of action. Regarding the former, drugs can exert their action in the tumor cell, the tumor vasculature, the immune system, or the endocrine system. The mechanism of action refers to the molecular target.

Patients with advanced malignant melanoma (MM) often do not receive satisfactory treatment. The present study reports the case of a 51-year-old female patient with stage IV MM of unknown primary. After undergoing immune checkpoint inhibitor therapy, the patient received multiple doses of hypofractionated radiotherapy (HFRT) for the left inguinal lymph node and single-fraction high-dose-rate brachytherapy for the left and right lung metastases. After combination treatment, the patient experienced almost complete remission of the inguinal target area, significant relief of pain and discomfort and an improved quality of life. The time of lung radiotherapy lesion control was 8 months. Meanwhile, the observed lesions (observation lesions 1, 2, 3 and 5) adjacent to the target lesion received lower doses of scattering (0.9-1.8 Gy) and the time of control for these lung observation lesions was 9 months. In addition, restarting targeted therapy after cessation of other treatments due to myelosuppression resulted in a progression-free survival time of 6 months. Nevertheless, the patient developed new metastases in the brain and abdomen. The present case report demonstrates that high-dose radiotherapy combined with immunotherapy may be effective for local lesions and that multiple doses of HFRT may be superior to single-fraction high-dose-rate brachytherapy for certain patients. Low-dose scattering also shows improvement for local lesions. Furthermore, restarting targeted therapy may be effective in the presence of target sites. Thus, the present case report provides a possible therapeutic option for the treatment of advanced melanoma.