Myelofibrosis (MF) is a myeloproliferative neoplasm that is accompanied by driver JAK2, CALR, or MPL mutations in more than 90% of cases, leading to constitutive activation of the JAK-STAT pathway. MF is a multifaceted disease characterized by trilineage myeloid proliferation with prominent megakaryocyte atypia and bone marrow fibrosis, as well as splenomegaly, constitutional symptoms, ineffective erythropoiesis, extramedullary hematopoiesis, and a risk of leukemic progression and shortened survival. Therapy can range from observation alone in lower-risk and asymptomatic patients to allogeneic hematopoietic stem cell transplantation, which is the only potentially curative treatment capable of prolonging survival, although burdened by significant morbidity and mortality. The discovery of the JAK2 V617F mutation prompted the development of JAK inhibitors (JAKi) including the first-in-class JAK1/JAK2 inhibitor ruxolitinib and subsequent approval of fedratinib, pacritinib, and momelotinib. The latter has shown erythropoietic benefits by suppressing hepcidin expression via activin A receptor type 1 (ACVR1) inhibition, as well as reducing splenomegaly and symptoms. However, the current JAKi behave as anti-inflammatory drugs without a major impact on survival or disease progression. A better understanding of the genetics, mechanisms of fibrosis, cytopenia, and the role of inflammatory cytokines has led to the development of numerous therapeutic agents that target epigenetic regulation, signaling, telomerase, cell cycle, and apoptosis, nuclear export, and pro-fibrotic cytokines. Selective JAK2 V617F inhibitors and targeting of mutant CALR by immunotherapy are the most intriguing and promising approaches. This review focuses on approved and experimental treatments for MF, highlighting their biological background.

Immune checkpoint inhibitors (ICI) boost the endogenous anticancer immunity, evoking long-lasting anticancer responses in a subset of patients with solid tumors. Simultaneously, ICI are also associated with serious toxicities, impacting treatment duration and the quality of life. The proposed processes underlying ICI-related toxicity include T-cell activation and recruitment to non-tumor tissues, involvement of other immune cells and fibroblasts and the host' microbiome composition. However, the exact mechanisms of these processes remain incompletely understood, hindering clinicians' ability to predict and identify ICI-related toxicity in the early stages of treatment. Molecular imaging may play a role as a non-invasive biomarker, providing a tool to study ICI-related toxicity. This review discusses the applications of molecular imaging to answer questions regarding the mechanisms, detection, and prediction of ICI-related toxicity. Potential targets and the current state of development of suitable imaging techniques are discussed.

Interpreting follicular helper T cell (Tfh) markers in the skin is challenging, raising the question of whether their expression is physiological or pathological. This review has two objectives: (1) to summarize current knowledge on Tfh lymphocytes, including circulating Tfh (cTfh) and peripheral helper T cells (Tph), and (2) to propose a practical approach for analyzing Tfh-rich skin infiltrates. Our method consists of two complementary entry points: histological and clinical. The histological approach classifies infiltrates into three patterns: (1) predominantly T-cell proliferation, suggesting a reactive infiltrate or hematodermia, (2) mixed B- and T-cell populations with a diffuse architecture, raising suspicion of a primary cutaneous CD4-positive small/medium T-cell lymphoproliferative disorder or Tfh lymphoma (primary or secondary), (3) B-cell nodules within a diffuse T-cell infiltrate, characteristic of reactive lymphoid hyperplasia, marginal zone B-cell lymphoproliferative disorders, or marginal zone lymphomas. In these cases, anti-IgM and anti-IgD immunolabeling is useful. Beyond Tfh-associated lymphocytes, the expression patterns and intensity of some Tfh markers (e.g., PD-1 in Sézary syndrome) help in reaching a diagnosis. The clinical algorithm categorizes presentations into three groups: (1) a solitary nodule or plaque, (2) multiple lesions (papules, plaques, or nodules/tumors), and (3) diffuse plaques or erythroderma. These histological and clinical algorithms are intertwined and complementary, providing a structured approach to evaluate Tfh-rich infiltrates in the skin.

The long-term effects of doxorubicin (DOX) chemotherapy on thymic immune function in childhood cancer survivors remain inadequately understood. This study explores the immediate and delayed impacts of low-dose DOX on thymic immune populations using a juvenile mouse model. Male mice received intraperitoneal DOX injections (4 mg/kg/week) for three weeks, with evaluations performed at one- and five-weeks post treatment. Thymic samples were collected and analyzed using multi-parameter flow cytometry to assess changes in immune cell composition and phenotype. Additionally, real-time polymerase chain reaction (RT-PCR) was employed to measure gene expression of cytokines and senescence markers. One week after DOX administration, significant thymic atrophy was evident. While mature CD3+CD4+ T-cell frequency remained unchanged, CD3+CD8+ T-cells significantly increased, suggesting differential effects on T-cell subsets. PD1+ expression increased across naïve and memory CD4+ T-cell subsets, suggesting activation or exhaustion. Additionally, Ki67+ expression was elevated in naïve and memory CD8+ T-cells, indicating enhanced proliferation. Gene expression analysis revealed upregulation of Foxn1, Pax1, Ifnγ, and Il7 whereas Il6 and Il17 were downregulated. Furthermore, Cdkn1a (p21) expression was elevated, suggesting immune dysregulation and early immunosenescence. At five weeks, thymic weight rebounded; however, T-cell subsets displayed persistent perturbations. Central memory and effector memory CD4+ T-cells were reduced, while naïve CD4+ T-cells showed increased Ki67+ expression. In contrast, CD8+ T-cells subsets remained largely unchanged, except for a decrease in central memory cells. Although expression of thymus-related genes was normalized, p21 expression remained elevated, suggesting lingering immunosenescence. These findings highlight the complex effects of DOX, including acute thymic atrophy due to T-cell depletion, and a delayed recovery with persistent immunosenescence, underscoring the need for strategies to preserve immune function in childhood cancer survivors.

To evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumour activity of AMG 404, a fully human IgG1 monoclonal antibody targeting programmed cell death-1, in patients with advanced solid tumours.

First-in-human phase I study comprising eight dose expansion cohorts, including cohorts with microsatellite instability-high (MSI-H) tumours and non-small cell lung cancer with high programmed death-ligand 1 expression (NSCLC/PDL1-H, tumour proportion score ≥50%).

Conducted across 28 global sites.

This study enrolled adult patients with histologically or cytologically confirmed metastatic or locally advanced solid tumours not amenable to curative treatment with surgery or radiation. The inclusion criteria included a life expectancy of >3 months, ≥1 measurable or evaluable lesion per modified Response Evaluation Criteria in Solid Tumours (RECIST) V.1.1, an Eastern Cooperative Oncology Group performance status of ≤2 and adequate haematological, renal and hepatic function. Patients with prior treatment with checkpoint inhibitors, primary brain tumour or untreated or symptomatic brain metastases and leptomeningeal disease and history of other malignancy within the past 2 years were excluded.

The planned doses were 240 mg, 480 mg and 1050 mg of AMG 404 administered every 4 weeks (Q4W).

Primary endpoints were dose-limiting toxicities (DLTs), treatment-emergent adverse events, treatment-related adverse events, changes in vital signs and clinical laboratory tests. Secondary endpoints included PK parameters, incidence of antidrug (AMG 404) antibodies and antitumour activity assessed per modified RECIST V.1.1 (objective response, duration of response, progression-free survival (PFS), disease control and duration of stable disease).

A total of 171 patients were enrolled; 168 were treated. Median (range) follow-up was 36.3 weeks (1.6-137.1). No DLTs were observed. Grade 3 and serious treatment-related adverse events occurred in 16 (9.5%) and 12 (7.1%) patients, respectively. The 480 mg Q4W dose was selected as the recommended phase II dose. AMG 404 serum exposure increased approximately dose proportionally. The objective response rate (80% CI) was 19.6% (15.7-24.1) for the overall population and 36.6% (26.4-47.8) and 30.8% (14.2-‍52.3) for cohorts with MSI-H tumours (n=41) and NSCLC/PDL1-H (n=13), respectively. The overall disease control rate (80% CI) was 54.8% (49.5-59.9). The median (80% CI) PFS was 3.7 (3.5-4.5) months for the overall population and 14.8 (9.0-not estimable) and 4.4 (2.2-9.7) months for cohorts with MSI-H tumours and NSCLC/PDL1-H, respectively.

AMG 404 monotherapy was tolerable at the tested doses, with encouraging antitumour activity observed across tumour types.

NCT03853109.

Molecular proximity is a governing principle of biology that is essential to normal and disease-related biochemical pathways. At the cell surface, protein-protein proximity regulates receptor activation, inhibition and protein recycling and degradation. Induced proximity is a molecular engineering principle in which bifunctional molecules are designed to bring two protein targets into close contact, inducing a desired biological outcome. Researchers use this engineering principle for therapeutic purposes and to interrogate fundamental biological mechanisms. This Review focuses on the use of induced proximity at the cell surface for diverse applications, such as targeted protein degradation, receptor inhibition and activating intracellular signaling cascades. We see a rich future for proximity-based modulation of cell surface protein activity both in basic and translational science.

Alzheimer's disease (AD) represents the most prevalent form of dementia, characterized by progressive cognitive impairment and chronic neuroinflammation. Immune checkpoint inhibitors (ICIs), including anti-programmed cell death (PD)-1 and anti-PD-L1, signify a revolutionary advancement in cancer treatment by preventing T-cell exhaustion; however, their therapeutic application in AD presents a conundrum. Hypothesis: Recent preclinical studies indicate that PD-1 inhibition in AD mouse models induces an interferon-gamma (IFN-γ)-mediated response, leading to increased recruitment of monocyte-derived macrophages into the brain, enhanced clearance of amyloid-beta (Aβ) plaques, and improved cognitive performance. Nonetheless, this therapeutic effect is counterbalanced by the potential for exacerbated neuroinflammation, as PD-1/PD-L1 blockade may potentiate pro-inflammatory T helper (Th)1 and Th17 responses. In this review, we critically discuss the pertinent pro-inflammatory and neuroprotective facets of T cell biology in the pathogenesis of AD, emphasizing the potential for modulation of the PD-1/PD-L1 axis to influence both Aβ clearance and the dynamics of neuroinflammatory processes. In summary, we determine that ICIs are promising tools for reducing AD pathology and improving cognition. However, it is essential to refine treatment protocols and carefully select patients to optimize neuroprotective effects while adequately considering inflammatory risks.

Persisting programmed cell death-1 (PD-1) signaling impairs T cell effector function, which is highly associated with T cell exhaustion and immunotherapy failure. However, the mechanism responsible for PD-1 deubiquitination and T cell dysfunction remains unclear. Here, we show that ubiquitin-specific peptidase 24 (USP24) promotes PD-1 protein stability by removing K48-linked polyubiquitin. Increased interleukin-6 level transcriptionally activates the USP24 expression, which leads to PD-1 stabilization. Furthermore, USP24 deficiency reduces PD-1 levels in CD8+ T cells and attenuates EgfrL858R-driven lung tumorigenesis in Usp24C1695A catalytic deficient mice. Targeting PD-1 stability with the USP24-specific inhibitor USP24-i-101 boosts cytotoxic T cell activity, restrains lung tumor growth, and achieves superior therapeutic effects when combined with anti-CTLA4 immunotherapy. Clinically, patients with lung cancer exhibiting high USP24 expression in tumor-infiltrating CD8+ T cells display exhausted features and show unfavorable responses to immunotherapy. Our findings dissect the mechanism for regulating enhanced PD-1 stability in tumor-infiltrating CD8+ T cells and reveal USP24 as a potential target of antitumor immunotherapy.

Programmed cell death protein 1 (PD-1) is frequently detected in certain subsets of tumor cells, and our understanding of PD-1 signaling consequences has expanded to include control of tumor growth, stemness and drug resistance. Nonetheless, tumor cell-intrinsic PD-1 has been comparatively underexplored in relation to PD-1 expressed on the surface of immune cells as an immune checkpoint, despite the imperative need to comprehensively elucidate the underlying mechanisms of action for achieving optimal responses in tumor immunotherapy. Here, we review the roles of the regulation and function of tumor-intrinsic PD-1 from its expression to degradation processes. Our primary focus is on unraveling its enigmatic influence on tumorigenesis and progression as proposed by recent findings, while navigating the labyrinthine network of regulatory mechanisms governing its expression and intricate functional interplay. We also discuss how the elucidation of the mechanistic underpinnings of tumor-intrinsic PD-1 expression holds the potential to explain the divergent therapeutic outcomes observed with anti-PD-1-based combination therapies, thereby furnishing indispensable insights crucial for synergistic anti-tumor strategies.

Background/Objectives: Peripheral neuroblastic tumors (pNT) are a biologically heterogeneous group of embryonal tumors that derive from the neural crest and affect the sympathetic nervous system. So far, little is known about the complex immune landscape in these rare childhood cancers. Methods: We focused on the immune cell infiltrate of treatment-naïve pNT from 24 patients, including high-risk neuroblastoma (HR-NBL), non-high-risk neuroblastoma (NHR-NBL), ganglioneuroblastoma (GNBL), and rare ganglioneuroma (GN). To gain novel insights into the immune architecture of these pNT subtypes, we used multiplex immunohistochemistry, multispectral imaging, and algorithm-based data evaluation to detect and characterize T cells, B cells, neutrophils, macrophages, and tertiary lymphoid structures (TLS). Results: The majority of the investigated tumor-infiltrating immune cells were macrophages and T cells. Their detailed phenotypic characterization revealed high proportions of M2-like macrophages as well as activated GrzB+ CD8+ and PD-1+ T lymphocytes. Proportions of these T cell phenotypes were significantly increased in GN compared to HR-NBL, NHR-NBL, or GNBL. In addition, TLS occurred in 11 of 24 patients, independent of immune cell frequencies in the whole tissues. Interestingly, all GN, most GNBL, but only a few NBL contained TLS. We distinguished between three TLS maturation stages that were present irrespective of the pNT subtype. The majority belonged to mature TLS of the primary follicle state. Mature LAMP3+ dendritic cells were also found, predominantly in T cell zones of TLS. Furthermore, TLS presence identified pNT patients with significantly prolonged progression-free survival in contrast to all other analyzed immunological features. Conclusions: We propose TLS to be a potential prognostic marker for pNT to predict patient outcomes.

Head and neck cancer (HNC) is the sixth most prevalent type of cancer worldwide and is associated with low five-year survival rates. Alcoholism and smoking are the main risk factors associated with the development of head and neck cancer (HNC). However, Human Papillomavirus (HPV) infection has been reported as a significant risk factor, particularly for the oropharyngeal subset. In these cases, patients with HPV-positive HNC exhibit a better clinical prognosis; however, resistance to chemotherapy has been frequently reported. The carcinogenic activity of HPV is related to the viral oncoproteins E5, E6, and E7. E5 has been associated with immune evasion mechanisms and modulation of the tumor microenvironment, which appears to be linked to the virus's resistance to chemotherapeutic treatments. Here, we review the potential of HPV E5 in targeted therapy for HNC and discuss relevant data regarding the activity of this oncoprotein in head and neck carcinogenesis.

Ubiquitin fold modifier 1 (UFM1) is a newly identified post-translational modifier that is involved in the UFMylation process. Similar to ubiquitination, UFMylation enables the conjugation of UFM1 to specific target proteins, thus altering their stability, activity, or localization. UFM1 chains have the potential to undergo cleavage from their associated proteins via UFM1-specific proteases, thus highlighting a reversible feature of UFMylation. This modification is conserved across nearly all eukaryotic organisms, and is associated with diverse biological activities such as hematopoiesis and the endoplasmic reticulum stress response. The disruption of UFMylation results in embryonic lethality in mice and is associated with various human diseases, thus underscoring its essential role in embryonic development, tissue morphogenesis, and organismal homeostasis. In this review, we aim to provide an in-depth overview of the UFMylation system, its importance in disease processes, and its potential as a novel target for therapeutic intervention.

In solid tumors, the tumor microenvironment (TME) is a complex mix of tumor, immune, stromal cells, fibroblasts, and the extracellular matrix. Cytotoxic T lymphocytes (CTLs) constitute a fraction of immune cells that may infiltrate into the TME. The primary function of these T-cells is to detect and eliminate tumor cells. However, due to the immunosuppressive factors present in the TME primarily mediated by Myeloid-Derived Suppressor Cells (MDSCs), Tumor associated macrophages (TAMs), Cancer Associated Fibroblasts (CAFs) as well as the tumor cells themselves, T-cells fail to differentiate into effector cells or become dysfunctional and are unable to eliminate the tumor. In addition, chronic antigen stimulation within the TME also leads to a phenomenon, first identified in chronic lymphocytic choriomeningitis virus (LCMV) infection in mice, where the T-cells become exhausted and lose their effector functions. Exhausted T-cells (Tex) are characterized by the presence of remarkably conserved inhibitory receptors, transcription and signaling factors and the downregulation of key effector molecules. Tex cells have been identified in various malignancies, including melanoma, colorectal and hepatocellular cancers. Recent studies have indicated novel strategies to reverse T-cell exhaustion. These include checkpoint inhibitor blockade targeting programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), or combinations of different immune checkpoint therapies (ICTs) or combination of ICTs with cytokine co-stimulation. In this review, we discuss aspects of T-cell dysfunction within the TME with a focus on T-cell exhaustion. We believe that gaining insight into the mechanisms of T-cell exhaustion within the TME of human solid tumors will pave the way for developing therapeutic strategies to target and potentially re-invigorate exhausted T-cells in cancer.

Immune checkpoint inhibition is a major component in today's cancer immunotherapy. In recent years, the FDA has approved a number of immune checkpoint inhibitors (ICIs) for the treatment of melanoma, non-small-cell lung, breast and gastrointestinal cancers. These inhibitors, which target cytotoxic T-lymphocyte antigen-4, programmed cell death (PD-1), and programmed cell death ligand (PD-L1) checkpoints have assumed a leading role in immunotherapy. The same inhibitors exert significant antitumor effects by overcoming tumor cell immune evasion and reversing T-cell exhaustion. The initial impact of this therapy in cancer treatment was justly described as revolutionary, however, clinical as well as research data which followed demonstrated that these innovative drugs are costly, are associated with potentially severe adverse effects, and only benefit a small subset of patients. These limitations encouraged enhanced research and clinical efforts to identify predictive biomarkers to stratify patients who are most likely to benefit from this form of therapy. The discovery and characterization of this class of biomarkers is pivotal in guiding individualized treatment against various forms of cancer. Currently, there are three FDA-approved predictive biomarkers, however, none of which on its own can deliver a reliable and precise response to immune therapy. Present literature identifies the absence of precise predictive biomarkers and poor understanding of the mechanisms behind tumor resistance as the main obstacles facing ICIs immunotherapy. In the present text, we discuss the dual role of PD-L1 as a biomarker for response to immunotherapy and as an immune checkpoint. The contribution of mass spectrometry-based analysis, particularly the impact of protein post-translational modifications on the performance of this protein is underlined.

Immunotherapy targeting immune checkpoints has gained traction across various cancer types in clinical settings due to its notable advantages. Despite this, the overall response rates among patients remain modest, alongside issues of drug resistance and adverse effects. Hence, there is a pressing need to enhance immune checkpoint blockade (ICB) therapies. Post-translational modifications (PTMs) are crucial for protein functionality. Recent research emphasizes their pivotal role in immune checkpoint regulation, directly impacting the expression and function of these key proteins. This review delves into the influence of significant PTMs-ubiquitination, phosphorylation, and glycosylation-on immune checkpoint signaling. By targeting these modifications, novel immunotherapeutic strategies have emerged, paving the way for advancements in optimizing immune checkpoint blockade therapies in the future.

Liver transplantation (LT) is a curative strategy for hepatocellular carcinoma (HCC), but the risk of HCC recurrence remains a challenging problem. In patients with HCC recurrence after LT (HCC-R_LT), the locoregional and surgical approaches are complex, and the guidelines do not report evidence-based strategies for the management of immunosuppression. In recent years, immunotherapy has become an effective option for patients with advanced HCC in pre-transplant settings. However, due to the risk of potentially fatal allograft rejection, the use of immunotherapy is avoided in post-transplant settings. Combining immunosuppressants with immunotherapy in transplant patients is also challenging due to the complex tumor microenvironment and immunoreactivity. The fear of acute liver rejection and the lack of predictive factors hinder the successful clinical application of immunotherapy for post-liver transplantation HCC recurrence. This review aims to comprehensively summarize the risk of HCC-R_LT, the available evidence for the efficacy of immunotherapy in patients with HCC-R_LT, and the clinical issues regarding the innovative management of this patient population.

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.

Personalized cancer vaccines (PCVs) can generate circulating immune responses against predicted neoantigens1-6. However, whether such responses can target cancer driver mutations, lead to immune recognition of a patient's tumour and result in clinical activity are largely unknown. These questions are of particular interest for patients who have tumours with a low mutational burden. Here we conducted a phase I trial (ClinicalTrials.gov identifier NCT02950766) to test a neoantigen-targeting PCV in patients with high-risk, fully resected clear cell renal cell carcinoma (RCC; stage III or IV) with or without ipilimumab administered adjacent to the vaccine. At a median follow-up of 40.2 months after surgery, none of the 9 participants enrolled in the study had a recurrence of RCC. No dose-limiting toxicities were observed. All patients generated T cell immune responses against the PCV antigens, including to RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA. Following vaccination, there was a durable expansion of peripheral T cell clones. Moreover, T cell reactivity against autologous tumours was detected in seven out of nine patients. Our results demonstrate that neoantigen-targeting PCVs in high-risk RCC are highly immunogenic, capable of targeting key driver mutations and can induce antitumour immunity. These observations, in conjunction with the absence of recurrence in all nine vaccinated patients, highlights the promise of PCVs as effective adjuvant therapy in RCC.

This study explored sex differences between dietary inflammatory index (DII) and cancer prognosis and their mechanisms. We hypothesized that association between dietary inflammatory index and cancer prognosis differs by sex. The study included 2874 adults with cancer from the National Health and Nutrition Examination Survey covering 1999 to 2014. Mortality status was linked to National Death Index mortality data through 31 December 2019. Cox proportional hazards regression models were applied to calculate hazard risk and 95% confidence intervals (Cis) in male patients and female patients. Sex-specific cancer and nonsex-specific cancer subgroup analyses were performed, and the role of C-reactive protein in sex differences was analyzed. The Cancer Genome Atlas pan-cancer transcriptome data were combined to explore the biological mechanisms of the sex differences. Multivariate Cox regression showed higher DII in male patients correlated with increased all-cause mortality (hazard risk highest vs lowest quartile = 1.57 [95% confidence intervals 1.24-1.98]; P for trend <.01), but not in female patients (P = .44). For sex-specific cancers, higher DII potentially correlated with increased mortality in prostate cancer (unadjusted P for trend = .04), but not in breast (P = .83), ovarian (P = .49), or cervical cancers (P = .91). In melanoma and colon cancer, higher DII correlated with increased mortality in male patients but not female patients. Serum C-reactive protein, interleukin-1 binding, interleukin-35 pathway, and programmed cell death protein 1 pathway may contribute to these sex differences. In conclusion, sex differences exist between DII and mortality risk in cancer patients.

The battle against cancer has evolved over centuries, from the early stages of surgical resection to contemporary treatments including chemotherapy, radiation, targeted therapies, and immunotherapies. Despite significant advances in cancer treatment over recent decades, these therapies remain limited by various challenges. Immune checkpoint inhibitors (ICIs), a cornerstone of tumor immunotherapy, have emerged as one of the most promising advancements in cancer treatment. Although ICIs, such as CTLA-4 and PD-1/PD-L1 inhibitors, have demonstrated clinical efficacy, their therapeutic impact remains suboptimal due to patient-specific variability and tumor immune resistance. Cell death is a fundamental process for maintaining tissue homeostasis and function. Recent research highlights that the combination of induced regulatory cell death (RCD) and ICIs can substantially enhance anti-tumor responses across multiple cancer types. In cells exhibiting high levels of recombinant solute carrier family 7 member 11 (SLC7A11) protein, glucose deprivation triggers a programmed cell death (PCD) pathway characterized by disulfide bond formation and REDOX (reduction-oxidation) reactions, termed "disulfidptosis." Studies suggest that disulfidptosis plays a critical role in the therapeutic efficacy of SLC7A11high cancers. Therefore, to investigate the potential synergy between disulfidptosis and ICIs, this study will explore the mechanisms of both processes in tumor progression, with the goal of enhancing the anti-tumor immune response of ICIs by targeting the intracellular disulfidptosis pathway.

Cancer treatment underwent significant changes in the last few years with the introduction of novel treatments targeting the immune system.

The objective of this review is to discuss novel anticancer drugs including kinase inhibitors, biologics and cellular therapy with CAR-T cells.

Most recent research articles were extracted from PubMed using keywords such as "kinases inhibitors", "CAR-T cell therapy".

The number of kinase inhibitors is significantly increasing due to their demonstrated effectiveness in combination with biologics. CAR-T represented a major breakthrough in the field. Also, it focused on their mechanisms of action and the rational of their use either alone or in combination in relation to their modes of action.

Colorectal cancer (CRC) is the third most prevalent form of cancer worldwide. Among patients with CRC, colorectal liver metastasis (CRLM) is the foremost direct contributor to mortality. In recent years, immunotherapy has swiftly risen to prominence as a vital approach for treating a range of solid tumors, including CRC. We present a unique case of a patient suffering from CRLM, with the goal of offering an insightful example and relevant references for the treatment of CRLM.

We report a patient who experienced liver metastasis after undergoing successful surgical removal of CRC, with the postoperative pathological stage identified as pT4N2aM0. The patient has been receiving a combination treatment of Western and Traditional Chinese Medicine. Regular assessments of the patient's condition have been conducted, encompassing evaluations of serum carcinoembryonic antigen levels, carbohydrate antigen 199, and observations of the tongue complexion and its coating. The patient achieved clinical remission after anti-programmed death-1 immunotherapy when various systemic therapies failed. Since the diagnosis of CRLM, the patient has survived for more than 6 years, surpassing the expected survival time for those with advanced CRC.

This case illustrates the considerable promise of anti-programmed death-1 immunotherapy in managing CRLM, especially in scenarios of drug resistance and disease progression.

Endothelial cells (ECs) are an initial barrier between vascularized organ allografts and the host immune system and are thus well positioned to initiate and influence alloimmune rejection. The mammalian target of rapamycin inhibitor rapamycin is known to inhibit T cell activation and attenuate acute allograft rejection. It also has numerous effects on ECs. We hypothesized that A mammalian target of rapamycin blockade might directly alter EC alloimmunogenicity and reduce alloimmune responses independent of its effects on T cell function. Here we report that rapamycin treatment modulates EC coinhibitory ligand expression and alters cytokine/chemokine production. It alters the EC transcriptome broadly associated with negative regulation of immune responses. Rapamycin-treated ECs suppress EC-specific T cell proliferation independent of programmed cell death 1/programmed death-ligand interaction and inhibit T cells responding to adjacent allogeneic cells in a contact-independent manner via secreted inhibitory mediators above 10 kDa. The T cell hyporesponsiveness induced by rapamycin-pretreated ECs was rescued by exogenous interleukin 2. Preexposing donor hearts to rapamycin improves the effect of B7 costimulation blockade in prolonging heart allograft survival in a major histocompatibility complex-mismatched mouse model. Our results indicate that rapamycin-treated ECs have reduced alloimmunogenicity and created a local, contact-independent environment that limits T cell alloreactivity via anergy induction and improves the efficacy of B7 costimulation blockade.

The annual rise in gastrointestinal cancer cases is evident, yet the occurrence of multiple primary malignancies remains comparatively uncommon. In recent years, immunotherapy has swiftly emerged as the leading treatment for several solid tumors, including gastrointestinal cancers. Single treatments might be ineffective, necessitating the need for comprehensive integrative medicine.

This study reports a case of multiple cancers, including colorectal and gastric cancers. Diverse systemic treatments, like capecitabine, the combination of capecitabine and paclitaxel liposome, as well as capecitabine with toripalimab, were unsuccessful. Nevertheless, prolonged survival was attained through anti-PD-1 immunotherapy complemented by alternative medicine approaches. The patient has exceeded a 35-month survival post-initial diagnosis and 20-month survival since the subsequent diagnosis, markedly surpassing the prognosis often associated with advanced-stage multiple cancers.

In summary, this case underscores the potential effectiveness of a holistic, integrative medical approach in managing advanced multiple malignancies amid drug resistance and disease progression.

ALK-rearranged renal cell carcinoma (ALK-RCC) is a rare malignant epithelial tumor of the kidney. ALK-RCC has recently been listed in the 5th edition of the World Health Organization (WHO) Classification of Tumors as a molecularly defined RCC subtype.

We describe retrospectively 3 ALK-RCCs from clinicopathologic, immunohistochemical (IHC), and molecular genetic aspects, along with postoperative adjuvant therapeutic regime and prognosis-related information.

Two patients were female and one patient was male. Patients' age ranged from 38 to 64 years (mean 51.3 years). Tumor size ranged from 32 mm to 89 mm (mean 55.3 mm, median 45 mm). All 3 tumors were diffusely positive for ALK protein. ALK fusion partners (TPM3 for case 1, VCL for case 2, and EML4 for case 3) were identified by next-generation sequencing. Histomorphologically, the tumors were heterogeneous, showing tubulocystic, papillary, trabecular, and solid growth patterns and polygonal to rhabdoid neoplastic cells. Cases 1 and 3 set in a mucinous background. Upon quantification of tumor-associated CD8+ T cells by IHC, tumor immune phenotypes (IPs) were defined as immune-desert in case 1, immune-inflamed in case 2, and immune-excluded in case 3. Follow-up for the 3 patients ranged from 18 to 129 months (mean, 59.3 months). Case 1 refused postoperative adjuvant therapy and was alive without disease at 129-month follow-up. Case 2 was postoperatively treated with a PD-1-targeted monoclonal antibody, being alive without disease at 18-month follow-up. Case 3 showed retroperitoneal lymph nodes and lung metastases at initial diagnosis. She was postoperatively treated with a PD-1-targeted monoclonal antibody, with no benefit suggested by computed tomography on follow-up.

ALK-RCC represents a distinct entity with clinicopathological, genetic, and immunophenotypic heterogeneity. ALK IHC analysis during primary screening may aid diagnosis in difficult cases. For progressive ALK-RCCs, postoperative adjuvant immunotherapy may be best selected according to IP features. Patients with immune-excluded phenotypes may not benefit from immunotherapy.

The PD1/PD-L1 axis plays an important immunosuppressive role during the T-cell-mediated immune response, which is essential for the physiological homeostasis of the immune system. The biology of the immunological microenvironment is extremely complex and crucial for the development of treatment strategies for immunotherapy. Characterization of the immunological, genomic or transcriptomic landscape of cancer patients could allow discrimination between responders and non-responders to anti-PD-1/PD-L1 therapy. Immune checkpoint inhibitor (ICI) therapy has shown remarkable efficacy in a variety of malignancies in landmark trials and has fundamentally changed cancer therapy. Current research focuses on strategies to maximize patient selection for therapy, clarify mechanisms of resistance, improve existing biomarkers, including PD-L1 expression and tumor mutational burden (TMB), and discover new biomarkers. In this review, we focus on the function of the PD-1/PD-L1 signaling pathway and discuss the immunological, genomic, epigenetic and transcriptomic landscape in cancer patients receiving anti-PD-1/PD-L1 therapy. Finally, we provide an overview of the clinical trials testing the efficacy of antibodies against PD-1/PD-L1.

Despite the unprecedented therapeutic potential of immune checkpoint antibody therapies, their efficacy is limited partly by the dysfunction of T cells within the cancer microenvironment. Combination therapies with small molecules have also been explored, but their clinical implementation has been met with significant challenges. To search for antitumor immunity activators, the present study developed a cell-based system that emulates cancer-attenuated T cells. The cell-based screening of 232 natural products containing electrophilic reactive functional groups led to the identification of arvenin I, also known as cucurbitacin B 2-O-β-d-glucoside (CuBg), as a plant natural product that activates T cells within the cancer-competitive environment. Chemoproteomic and mechanistic analyses indicated that arvenin I covalently reacts with and hyperactivates MKK3, thereby reviving the mitochondrial fitness of exhausted T cells through the activation of the p38MAPK pathway. In mice, administration of arvenin I enhanced the efficacy of cancer immunotherapy when used alone or in combination with an immune checkpoint inhibitor. These findings highlight the potential of arvenin I as a covalent kinase activator that potentiates antitumor immunity.

Immune checkpoint molecules, including both co-inhibitory molecules and co-stimulatory molecules, are known to play critical roles in regulating T-cell responses. During the last decades, immunotherapies targeting these molecules (such as programmed cell death 1 (PD-1), and lymphocyte activation gene 3 (LAG-3)) have provided clinical benefits in many cancers. It is becoming apparent that not only T cells, but also B cells have a capacity to express some checkpoint molecules. These were originally thought to be only the markers for regulatory B cells which produce IL-10, but recent studies suggest that these molecules (especially T-cell immunoglobulin and mucin domain 1 (TIM-1), T cell immunoreceptor with Ig and ITIM domains (TIGIT), and PD-1) can regulate intrinsic B-cell activation and functions. Here, we focus on these molecules and summarize their characteristics, ligands, and functions on B cells.

Background: Lung malignancies, including cancerous lymphangitis and lymphomas, can mimic interstitial lung diseases like cryptogenic organizing pneumonia (COP) on imaging, leading to diagnostic delays. We aimed to identify potential biomarkers to distinguish between these conditions. Methods: We analyzed bronchoalveolar lavage fluid from 8 patients (4 COP, mean age 59.8 ± 13.5 years; 4 lung malignancies including 2 cancerous lymphangitis, 1 MALT lymphoma, and 1 diffuse large B cell lymphoma, mean age 67.8 ± 4.5 years) using mass cytometry with 35 T cell markers. Data were analyzed using principal component analysis (PCA) and unsupervised Citrus clustering. Results: PCA of T cell marker intensities effectively separated the two groups, with IL-2Rα, PD-L2, CD45RA, CD44, and OX40 being the top discriminating markers. Citrus analysis showed a significant increase in the CD16+ CD4+ and CD16+ CD8+ T cell populations in the COP group compared to lung malignancies. Conclusions: Our findings reveal distinct T cell immunophenotypes in COP versus lung malignancies, particularly increased CD16+ T cells in COP, which could serve as potential diagnostic biomarkers.

Merkel cell carcinoma (MCC) is a skin cancer that arises due to either Merkel cell polyomavirus infection (MCPyV) or ultraviolet (UV) radiation exposure, presenting primarily in the head and neck region of fair-skinned males. The recent success of PD-(L)1 immune checkpoint inhibitors (ICIs) in locally advanced/metastatic MCC, with an objective response rate (ORR) around 50% and improved survival, as a first-line treatment has moved ICIs to the forefront of therapy for MCC and generated interest in identifying biomarkers to predict clinical response. The MCC tumour microenvironment (TME) contains various components of the adaptive and innate immune system. These components can contribute to tumour immune escape through immunosuppression by preventing entrance of other immune cells or by aiding in the cytotoxic clearance of tumour cells. We aim to combine information from studies of baseline and on-treatment monitoring of the TME to help predict the success of ICIs in MCC. This review enhances the understanding of how CD8 T cells, γδ T cells and macrophages may impact predictions of response rates to ICIs in MCC patients. These immune cells are non-genetic biomarkers that can also be used to determine prognosis in MCC treatment.

Since the discovery and characterization of the PD-1/PD-L pathway, mounting evidence has emerged regarding its role in regulating neuroinflammation following cerebrovascular injury. Classically, PD-L1 on antigen-presenting cells or tissues binds PD-1 on T cell surfaces resulting in T cell inhibition. In myeloid cells, PD-1 stimulation induces polarization of microglia and macrophages into an anti-inflammatory, restorative phenotype. The therapeutic potential of PD-1 agonism in ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage-related vasospasm, and traumatic brain injury rests on the notion of harnessing the immunomodulatory function of immune checkpoint pathways to temper the harmful effects of immune overactivation and secondary injury while promoting repair and recovery. Immune checkpoint agonism has greater specificity than the wider and non-specific anti-inflammatory effects of other agents, such as steroids. PD-1 agonism has already demonstrated success in clinical trials for rheumatoid arthritis and is being tested in other chronic inflammatory diseases. Further investigation of PD-1 agonism as a therapeutic strategy in cerebrovascular injury can help clarify the mechanisms underlying clinical benefit, develop drugs with optimal pharmacodynamic and pharmacokinetic properties, and mitigate unwanted side effects.

Targeting the PD-1/PD-L1 axis with small-molecular inhibitors is a promising approach for immunotherapy. Here, we identify a natural pentacyclic triterpenoid, Pygenic Acid A (PA), as a PD-1 signaling inhibitor. PA exerts anti-tumor activity in hPD-1 knock-in C57BL/6 mice and enhances effector functions of T cells to promote immune responses by disrupting the PD-1 signaling transduction. Furthermore, we identify SHP-2 as the direct molecular target of PA for inhibiting the PD-1 signaling transduction. Subsequently, mechanistic studies suggest that PA binds to a new druggable site in the phosphorylated PD-1 ITSM recognition site of SHP-2, inhibiting the recruitment of SHP-2 by PD-1. Taken together, our findings demonstrate that PA has a potential application in cancer immunotherapy and occupying the phosphorylated ITSM recognition site of SHP-2 may serve as an alternative strategy to develop PD-1 signaling inhibitors. In addition, our success in target recognition provides a paradigm of target identification and confirmation for natural products.

Exhausted T cell (Tex) is a specific state of T cell dysfunction, in which these T cells gradually lose their effector function and change their phenotype during chronic antigen stimulation. The enrichment of exhausted CD8+ T cell (CD8+ Tex) in the tumor microenvironment is one of the important reasons leading to the poor efficacy of immunotherapy. Recent studies have reported many reasons leading to the CD8+ T cell exhaustion. In addition to cancer cells, myeloid cells can also contribute to T cell exhaustion via many ways. In this review, we discuss the history of the concept of exhaustion, CD8+ T cell dysfunction states, the heterogeneity, origin, and characteristics of CD8+ Tex. We then focus on the effects of myeloid cells on CD8+ Tex, including tumor-associated macrophages (TAMs), dendritic cells (DCs) and neutrophils. Finally, we systematically summarize current strategies and recent advancements in therapies reversing and CD8+ T cell exhaustion.

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.