Activation of the RAS/MAPK pathway is associated with reduced tumor-infiltrating lymphocytes and poor outcomes in triple-negative breast cancer. Previous studies demonstrated that inhibition of the MAPK pathway with a MEK inhibitor is synergistic with immune checkpoint inhibitors.

We conducted a phase I/II trial of pembrolizumab and binimetinib in patients with metastatic triple-negative breast cancer with ≤3 prior lines of therapy. There were two dose levels (DL) with binimetinib at 45 mg at DL 0 and 30 mg at DL -1.

The recommended phase II dose was the standard dose of pembrolizumab with binimetinib 30 mg twice daily. The objective response rate (ORR) was 30.4%, with a numerically higher ORR in patients without liver metastasis at 45.5%. Among patients who achieved objective responses, 80% had a duration of response >12 months and ongoing even after stopping treatment (5.4-69.0 months). Patients with PD-L1-positive tumors (modified proportion score ≥10) were more likely to respond with an ORR of 66.7%. However, clinical benefit was observed in 25% of patients with PD-L1-negative tumors. Consistent with preclinical studies, four of six patients with clinical benefit had either increased PD-L1 or decreased p-ERK expressions in serial circulating cancer-associated macrophage-like cells after starting binimetinib.

Pembrolizumab and binimetinib at 30 mg are safe with manageable toxicities. Promising activity was observed in patients without liver metastases. Future larger clinical trials are warranted to further evaluate the efficacy of this chemotherapy-free combination.

Lung cancer is one of the most common malignant tumors, of which non-small cell lung cancer (NSCLC) accounts for about 85 %. Although immune checkpoint inhibitors (ICIs), particularly PD-1/PD-L1 inhibitors, have significantly improved the prognosis of patients with NSCLC. There are still many patients do not benefit from ICIs. Primary resistance remains a major challenge in advanced NSCLC. The cancer-immunity cycle describes the process from antigen release to T cell recognition and killing of the tumor, which provides a framework for understanding anti-tumor immunity. The classical cycle consists of seven steps, and alterations at each stage can result in resistance. This review examines the current status of PD-1/PD-L1 blockade in the treatment of advanced NSCLC and explores potential mechanisms of resistance. We summarize the latest clinical trials of PD-1/PD-L1 inhibitors combined with other therapies and explore potential targets for overcoming primary resistance to PD-1/PD-L1 inhibitors.

Neoadjuvant treatment has become standard for patients with high-risk operable stage III melanoma, but the optimal regimen is unknown. Targeted therapy approaches yield high pathological response rates, while immunotherapy regimens show favorable recurrence-free survival (RFS). NeoACTIVATE was designed to address whether a neoadjuvant combination of both targeted therapy and immunotherapy might leverage the benefits of each.

We tested neoadjuvant treatment with 12 weeks of vemurafenib, cobimetinib, and atezolizumab for patients with BRAF-mutated (BRAFm) melanoma (cohort A) and cobimetinib and atezolizumab for patients with BRAF-wild-type (BRAFwt) melanoma (cohort B), regimens which we have shown generate a substantial major pathological response. After therapeutic lymph node dissection, patients received 24 weeks of adjuvant atezolizumab. Here, we report survival outcomes and their association with biomarkers assayed among the gut microbiome and peripheral blood immune subsets.

With 49 months median follow-up, the median RFS was not reached for cohort A and was 40.8 months for cohort B. At 24 months after operation, 2 of 14 cohort A patients and 4 of 13 cohort B patients had experienced distant relapse. Key findings from correlative analyses included diversity, taxonomic and functional metagenomic gut microbiome signals associated with distant metastasis-free survival at 2 years. Notably, we observed a strong correlation between low microbial arginine biosynthesis (required for T-cell activation and effector function) and early distant recurrence (p=0.0005), which correlated with taxonomic differential abundance findings. Peripheral blood immune monitoring revealed increased double-positive (CD4+CD8+) T cells in patients with early recurrence.

Neoadjuvant treatment with cobimetinib and atezolizumab±vemurafenib was associated with a low rate of distant metastasis in patients with high-risk stage III melanoma. Freedom from early distant metastasis was highly associated with taxonomic differences in gut microbiome structure and with functional pathway alterations known to modulate T cell immunity. Identification of predictive biomarkers will permit optimization of neoadjuvant therapy regimens for individual patients.

NCT03554083.

Chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of hematologic malignancies. However, it continues to encounter significant obstacles, including treatment relapse and limited efficacy in solid tumors. While effector T cells exhibit robust cytotoxicity, central memory T cells and stem cell-like T cells are essential for in vivo expansion, long-term survival, and persistence. Strategies such as genetic engineering to enhance CAR-T cell efficacy and durability are often accompanied by increased safety risks, which not only raise regulatory approval thresholds but also escalate CAR-T production costs. In contrast, optimizing ex vivo manufacturing conditions represents a more straightforward and practical approach, offering the potential for rapid application to commercially approved CAR-T products and enhancement of their clinical outcomes. This review examines several factors that have been shown to improve T cell memory phenotype and in vivo cytotoxic activity, including cytokines, electrolytes, signaling pathway inhibitors, metabolic modulators, and epigenetic agents. The insights provided will guide the optimization of CAR-T cell industrial production. Furthermore, considerations for selecting appropriate conditions are discussed, balancing effectiveness, cost-efficiency, safety, and regulatory compliance while addressing current challenges in the field.

BRAF-mutated colorectal cancer correlates with poor prognosis and limited response to standard treatments. Combining immune checkpoint inhibitors with BRAF/MEK inhibitors shows promise against BRAF-mutant melanoma in both preclinical and clinical trials. Therefore, we hypothesized that the treatment would be effective against BRAF-mutant colorectal cancer. In this study, we assessed the efficacy of combining immune checkpoint inhibitors with BRAF and/or MEK inhibitors in BRAF-mutant colorectal cancers. We treated BRAF V600E colorectal cancer cells HT-29 and SNU-1235 with encorafenib (BRAF inhibitor) and binimetinib (MEK inhibitor) and assessed the degrees of MAPK inhibition, JAK/STAT inhibition, cell viability, apoptosis, and the expression of antigen presenting machinery. We also inoculated HT-29 cells into mice and treated them with an immune checkpoint inhibitor (durvalumab), encorafenib, and binimetinib for 4 weeks. We found that treatment with BRAF inhibitor, MEK inhibitor, or their combination led to significant tumor growth reduction, along with the MAPK and JAK/STAT pathway inhibition, antigen presenting machinery induction, and cytotoxic T cell activation. Our study demonstrates the potential effectiveness of combining immune checkpoint inhibitors with BRAF or MEK inhibitors for BRAF-mutated colorectal cancers.

To investigate the effect and molecular mechanism of ezetimibe on colorectal cancer (CRC), our study found that ezetimibe significantly inhibited the proliferation and progression of CRC. Further study showed that RPS6KA2 might be the target gene of ezetimibe treatment on CRC. RPS6KA2 expression was significantly lower in human CRC tissue samples and associated with T classification and vascular invasion of tumor cells. RPS6KA2 inhibited proliferation, migration, and invasion of CRC cells. The underlying mechanisms indicated that interaction between RPS6KA2 and PCSK9 was observed within the cytoplasmic compartment of CRC cells. RPS6KA2 suppressed PCSK9 and MAPK signaling pathway in CRC cells. BI-D1780 which is an inhibitor of RPS6KA2 increased PCSK9 and MAPK signaling pathway related proteins expression in SW620 cells. However, an inhibitor or stimulator of MAPK did not affect RPS6KA2 and PCSK9 expression, respectively. In vivo, CRC cells with RPS6KA2 or PCSK9 overexpression could inhibit or promote tumor growth and metastasis, respectively. PCSK9 promoted proliferation, migration, and invasion of CRC cells. PCSK9 expression was higher in human CRC samples and associated with N classification and TNM stage of CRC. In conclusion, our study firstly suggests that ezetimibe suppresses CRC progression by upregulating RPS6KA2 while downregulating PCSK9/MAPK signaling pathway.

CD28 ligation provides critical signals that modulate activated T cell fate. In a human to mouse reverse-engineering approach, a single amino acid substitution adjacent to the C-terminal proline-rich domain created CD28A210P mice with enhanced signaling. CD28A210P mice experienced pro-inflammatory responses to CD28 superagonist antibody, analogous to severe cytokine storm induced in a human clinical trial, with a striking increase of activated CD8 T cells. In acute and chronic viral infections, early activation and expansion of CD28A210P CD8 effector T cells increased, with accelerated exhaustion in chronic infection. Mechanistically, CD28A210P enhanced JunB, IL-2, and inhibitory receptors driven by MEK1/2. Generation of CD28A210P stem-like progenitor (Tpex) cells was enhanced in acute and chronic infections, and further expanded by PD-L1 blockade in chronically-infected mice. Thus, 'humanized' PYAP mice reveal key roles for CD28 signaling strength in CD8 activation, accelerating exhaustion during antigen persistence, while promoting and sustaining Tpex during acute and chronic viral infection.

Immune checkpoint inhibitors (CPIs) have revolutionized cancer therapy for several tumor indications. However, a substantial fraction of patients treated with CPIs derive no benefit or have short-lived responses to CPI therapy. Identifying patients who are most likely to benefit from CPIs and deciphering resistance mechanisms is therefore essential for developing adjunct treatments that can abrogate tumor resistance.

In this study, we used a machine learning approach that used the US-based nationwide de-identified Flatiron Health and Foundation Medicine non-small cell lung carcinoma (NSCLC) clinico-genomic database to identify genomic markers that predict clinical responses to CPI therapy. In total, we analyzed data from 4,433 patients with NSCLC.

Analysis of pretreatment genomic data from 1,511 patients with NSCLC identified. Of the 36 genomic signatures identified, 33 exhibited strong predictive capacity for CPI response (n=1150) compared with chemotherapy response (n=361), while three signatures were prognostic. These 36 genetic signatures had in common a core set of four genes (BRAF, BRIP1, FGF10, and FLT1). Interestingly, we observed that some (n=19) of the genes in the signatures (eg, TP53, EZH2, KEAP1 and FGFR2) had alternative mutations with contrasting clinical outcomes to CPI therapy. Finally, the genetic signatures revealed multiple biological pathways involved in CPI response, including MAPK, PDGF, IL-6 and EGFR signaling.

In summary, we found several genomic markers and pathways that provide insight into biological mechanisms affecting response to CPI therapy. The analyses identified novel targets and biomarkers that have the potential to provide candidates for combination therapies or patient enrichment strategies, which could increase response rates to CPI therapy in patients with NSCLC.

The importance of metabolic pathways in regulating immune responses is now well established, and a mapping of the bioenergetic metabolism of different immune cell types is under way. CD8 T cells and natural killer (NK) cells contribute to cancer immunosurveillance through their cytotoxic functions and secretion of cytokines and chemokines, complementing each other in target recognition mechanisms. Several immunotherapies leverage these cell types by either stimulating their activity or redirecting their specificity against tumour cells. However, the anticancer activity of CD8 T cells and NK cells is rapidly diminished in the tumour microenvironment, closely linked to a decline in their metabolic capacities. Various strategies have been developed to restore cancer immunosurveillance, including targeting bioenergetic metabolism or genetic engineering. This Review provides an overview of metabolic dysfunction in CD8 T cells and NK cells within the tumour microenvironment, highlighting current therapies aiming to overcome these issues.

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in patients with non-small cell lung cancer (NSCLC) lacking targetable oncogenic alterations. However, their efficacy in individuals with such genomic alterations remains heterogeneous and poorly understood. In detail, certain oncogenic alterations in TP53, EGFR (uncommon mutations), KRAS (G12C), BRAF (non-V600E), MET (amplifications), FGFR1 and FGFR4, actively modify MAPK, PI3K, and STING signaling, thus remodeling tumoral immune phenotype and are associated with high TMB counts, enriched T lymphocyte tumor infiltration, and high expression of antigen-presenting molecules, supporting their consideration as part of the eligibility criteria for ICIs treatment. Nonetheless, other oncogenic alterations are associated with an immunosuppressive TME, low TMB counts, and downregulation of targetable immune checkpoints, in which novel therapeutic approaches are currently being tested to overcome their intrinsic resistance. In this context, this review discusses the fundamental mechanisms by which frequent driver alterations affect ICIs efficacy in patients with NSCLC, and outlines their prognostic relevance in the era of immunotherapy.

Cholangiocarcinoma (CCA) is a diverse group of epithelial malignant tumors arising from the biliary tract, characterized by high molecular heterogeneity. It is classified into intrahepatic (iCCA) and extrahepatic CCA (eCCA) based on the location of the primary tumor. CCA accounts for approximately 15% of all primary liver cancers, with iCCA comprising 10-20% of all CCAs. iCCA is especially known for its characteristic aggressiveness and refractoriness, leading to poor prognosis. Despite the increasing global incidence and mortality rates, surgery remains the only available standard treatment approach for a subset (25%) of patients with early-stage, resectable iCCA. The paucity of effective systemic medical therapies restricts therapeutic options for patients with advanced or metastatic iCCA. In the past decade, advances in the understanding of the molecular complexity of these tumors have provided fruitful insights for the identification of promising new druggable targets and the development of feasible therapeutic strategies that may improve treatment outcomes for patients with iCCA. In this review, we aim to highlight critical up-to-date studies and medicinal chemistry aspects, focusing on novel targeted approaches utilizing promising candidates for molecular targeted therapy in iCCA. These candidates include aberrations in isocitrate dehydrogenase (IDH) 1/2, fibroblast growth factor receptor (FGFR), B-Raf proto-oncogene (BRAF), neurotrophic tyrosine receptor kinase (NTRK), human epidermal growth factor receptor 2 (HER2), and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1). Furthermore, this review provides an overview of potential inhibitors aimed at overcoming acquired drug resistance in these actionable targets for iCCA.

Although immune checkpoint inhibitor (ICI) therapy is currently the standard of care in microsatellite-unstable (MSI) metastatic colorectal cancer (CRC), ICI therapy, alone or in combination with other therapies, is not a treatment approach in microsatellite-stable (MSS) CRC, which is present in 95% of patients. In this review, we focus on metabolic singularities-at the transcriptomic (either bulk or single cell), proteomic, and post-translational modification levels-that induce immunosuppression in cancer and specifically in MSS CRC. First, we evaluate the current efficacy of ICIs in limited and metastatic disease in MSS CRC. Second, we discuss the latest findings on the potential biomarkers for evaluating ICI efficacy in MSS CRC using strict REMARK criteria. Third, we review the current evidence on metabolic patterns in CRC tumors and immune cell metabolism to advance our understanding of metabolic crosstalk and to pave the way for the development of combination strategies to enhance ICI efficacy.

Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. The discovery of specific driver mutations has revolutionized the treatment landscape of oncogene-addicted NSCLC through targeted therapies, significantly improving patient outcomes. However, immune checkpoint inhibitors (ICIs) have demonstrated limited effectiveness in this context. Emerging evidence, though, reveals significant heterogeneity among different driver mutation subgroups, suggesting that certain patient subsets may benefit from ICIs, particularly when combined with other therapeutic modalities. In this review, we comprehensively examine the current evidence on the efficacy of immunotherapy in oncogene-addicted NSCLC. By analyzing recent clinical trials and preclinical studies, along with an overview of mechanisms that may reduce immunotherapy efficacy, we explored potential strategies to address these challenges, to provide insights that could optimize immunotherapy approaches and integrate them effectively into the treatment algorithm for oncogene-addicted NSCLC.

Cancer remains a leading cause of mortality globally and a major health burden, with chemotherapy often serving as the primary therapeutic option for patients with advanced-stage disease, partially compensating for the limitations of non-curative treatments. However, the emergence of chemotherapy resistance significantly limits its efficacy, posing a major clinical challenge. Moreover, heterogeneity of resistance mechanisms across cancer types complicates the development of universally effective diagnostic and therapeutic approaches. Understanding the molecular mechanisms of chemoresistance and identifying strategies to overcome it are current research focal points. This review provides a comprehensive analysis of the key molecular mechanisms underlying chemotherapy resistance, including drug efflux, enhanced DNA damage repair (DDR), apoptosis evasion, epigenetic modifications, altered intracellular drug metabolism, and the role of cancer stem cells (CSCs). We also examine specific causes of resistance in major cancer types and highlight various molecular targets involved in resistance. Finally, we discuss current strategies aiming at overcoming chemotherapy resistance, such as combination therapies, targeted treatments, and novel drug delivery systems, while proposing future directions for research in this evolving field. By addressing these molecular barriers, this review lays a foundation for the development of more effective cancer therapies aimed at mitigating chemotherapy resistance.

Mitogen-activated extracellular signal-regulated kinase inhibitors (MEKi) represent a promising new therapy for pediatric patients with low-grade gliomas, which frequently have abnormal signaling within the mitogen-activated protein kinase (MAP kinase) pathway. However, understanding of long-term efficacy and toxicity is limited in pediatric glioma patients. This article describes a rare presentation of a widespread cutaneous infection with Mycobacterium chelonae in a pediatric patient with a low-grade glioma treated with trametinib.

Hematopoietic progenitor pinase1 (HPK1) knockout has been identified as an efficient route to enhance anti-tumor immune response. Here, this work develops an oral proteolysis targeting chimera (PROTAC) targeting HPK1 to efficiently and selectively degrade HPK1 to augment immunotherapeutic outcomes. In a postoperative tumor model of human cervical cancer in NSG mice, the orally-administrated PROTAC can reach tumors, down-regulate HPK1 levels in locally-administrated CAR-T cells, and promote their efficiency in inhibiting solid tumor recurrence, achieving 50% partial response (PR) and 50% complete response (CR). In addition, oral administration of PROTAC can amplify the suppression capability of the anti-PD-L1 antibody on the growth of CT26 solid tumors in BALB/c mice by promoting the infiltration of CD45-positive immune cells from 0.7% to 1.5% and CD3-positive T cells from 0.2% to 0.5% within the tumors.

An increasing body of research indicates that immunotherapy has demonstrated substantial effectiveness in the realm of metastatic colorectal cancer(mCRC), especially among patients with deficient mismatch repair (dMMR) or microsatellite instability-high (MSI-H) (dMMR/MSI-H mCRC). This study constitutes the inaugural bibliometric and visual analysis of immunotherapy related to mCRC during the last decade. Between 2013 and the conclusion of 2022, we screened 306 articles from Web of Science and subjected them to analysis using CiteSpace and VOSviewer. The United States stood out as the primary contributor in this area, representing 33.33% of the publications, with China following closely at 24.51%. The most prolific institution has the lowest average citation rate. Sorbonne University were the most highly cited institutions. Notably, Frontiers In Oncology published the largest quantity of articles. Andre, Thierry, and Overman, Michael J. were prominent authors known for their prolific output and the high citation rates of their work. The focus areas in this field encompass "tumor microenvironment," "liver metastasis," "tumor-associated macrophages," "combination therapy" and "gut microbiota." Some keywords offer promise as potential biomarkers for evaluating the effectiveness of immunotherapeutic interventions.

Immunotherapy is one of the research hotspots in colorectal cancer field in recent years. The colorectal cancer patients with mismatch repair-deficient (dMMR) or high microsatellite instability (MSI-H) are the primary beneficiaries of immunotherapy. However, the vast majority of colorectal cancers are mismatch repair proficient (pMMR) or microsatellite stability (MSS), and their immune microenvironment is characterized by "cold tumors" that are generally insensitive to single immunotherapy based on immune checkpoint inhibitors (ICIs). Studies have shown that some pMMR/MSS colorectal cancer patients regulate the immune microenvironment by combining other treatments, such as multi-target tyrosine kinase inhibitors, anti-vascular endothelial growth factor (VEGF) monoclonal antibodies, chemotherapy, radiotherapy, anti-epithelial growth factor receptor (EGFR) monoclonal antibodies, and mitogen-activated protein kinase (MAPK) signaling pathway inhibitors and oncolytic viruses, etc. to transform "cold tumor" into "hot tumor", thereby improving the response to immunotherapy. In addition, screening for potential prognostic biomarkers can also enrich the population benefiting from immunotherapy for microsatellite stable colorectal cancer. Therefore, in pMMR or MSS metastatic colorectal cancer (mCRC), the optimization of immunotherapy regimens and the search for effective efficacy prediction biomarkers are currently important research directions. In this paper, we review the progress of efficacy of immunotherapy (mainly ICIs) in pMMR /MSS mCRC, challenges and potential markers, in order to provide research ideas for the development of immunotherapy for mCRC.

Currently, only 20% to 40% of patients with cancer benefit from immune checkpoint inhibitors. Understanding the mechanisms underlying the immunosuppressive tumor microenvironment (TME) and characterizing dynamic changes in the immunologic landscape during treatment are critical for improving responsiveness to immunotherapy. In this study, we identified JNK signaling in cancer-associated fibroblasts (CAF) as a regulator of the immunosuppressive TME. Single-cell RNA sequencing of bladder cancer samples treated with a JNK inhibitor revealed enhanced cytotoxicity and effector functions of CD8+ T cells. In untreated tumors, CAFs interacted frequently with CD8+ T cells and mediated their exhaustion. JNK inhibition abrogated the immunosuppression function of CAFs by downregulating the expression of thymic stromal lymphopoietin (TSLP), thereby restoring CD8+ T-cell cytotoxicity. In addition, blockade of CAF-derived TSLP in combination with anti-PD-1 treatment promoted tumor elimination by CD8+ T cells in vivo. Collectively, these results indicate that JNK signaling plays an important immunosuppressive role in the TME by promoting expression of TSLP in CAFs and suggest that inhibiting JNK signaling could be a promising immunotherapeutic strategy for cancer treatment. Significance: JNK signaling promotes the secretion of TSLP by bladder cancer-associated fibroblasts to impede CD8+ T-cell activity, which can be circumvented by combination treatment targeting JNK signaling and PD-1.

Although rare in non-small cell lung cancer (NSCLC), BRAF mutations present considerable therapeutic challenges. While the use of BRAF and MEK inhibitor combinations has significantly improved survival outcomes in patients with BRAF V600E mutations, no targeted therapies are currently available for class II and III mutations, leaving the optimal treatment strategy and prognosis for these patients uncertain. Additionally, despite immunotherapy typically showing limited benefit in patients with other activating genomic alterations, it appears to deliver comparable efficacy in BRAF-mutated NSCLC, emerging as a potentially viable treatment option, particularly in patients with a history of smoking. However, resistance to BRAF pathway inhibitors is inevitable, leading to disease progression, and a well-defined strategy to overcome these resistance mechanisms is lacking. This review aims to explore the critical challenges in the management of BRAF-mutated NSCLC, providing a comprehensive summary of the current evidence and highlighting ongoing clinical trials that aim to address these critical gaps.

Colorectal cancer (CRC) with BRAF V600E mutation presents a formidable scientific and clinical challenge due to its aggressive nature and poor response to standard therapeutic approaches. BRAF V600E mutation-induced conspicuous activation of the MAPK pathway contributes to the relentless tumor progression. Nevertheless, the efficacy of multi-targeted MAPK pathway inhibition remains suboptimal in clinical practice. Patients with high microsatellite instability (MSI-H) have shown favorable results with immune checkpoint inhibitors (ICIs). The combination of the MAPK pathway inhibition with ICIs has recently emerged as a promising regimen to improve clinical outcomes in the microsatellite stable (MSS) subgroup of BRAF V600E-mutant metastatic CRC patients. In this review, we elucidate the unique tumor biology of BRAF V600E-mutant CRC, with a particular focus on the immune features underlying the rationale for ICI treatments in the MSI-H and MSS subpopulations, then highlight the trends in clinical trials of the ICI therapy for BRAF V600E-mutant metastatic CRC.

T cells are the main effectors involved in anti-tumor immunity, mediating most of the adaptive response towards cancer. After priming in lymph nodes, tumor antigens-specific naïve T lymphocytes proliferate and differentiate into effector CD4+ and CD8+ T cells that migrate from periphery into tumor sites aiming to eliminate cancer cells. Then while most effector T cells die, a small fraction persists and recirculates as long-lived memory T cells which generate enhanced immune responses when re-encountering the same antigen. A number of T (and non-T) cell subsets, stably resides in non-lymphoid peripheral tissues and may provide rapid immune response independently of T cells recruited from blood, against the reemergence of cancer cells. When tumor grows, however, tumor cells have evaded immune surveillance of effector cells (NK and CTL cells) which are exhausted, thus favoring the local expansion of T (and non-T) regulatory cells. In this review, the current knowledge of features of T cells present in the tumor microenvironment (TME) of solid adult and pediatric tumors, the mechanisms upregulating immune-checkpoint molecules and transcriptional and epigenetic landscapes leading to dysfunction and exhaustion of T effector cells are reviewed. The interaction of T cells with cancer- or TME non-neoplastic cells and their secreted molecules shape the T cell profile compromising the intrinsic plasticity of T cells and, therefore, favoring immune evasion. In this phase regulatory T cells contribute to maintain a high immunosuppressive TME thus facilitating tumor cell proliferation and metastatic spread. Despite the advancements of cancer immunotherapy, many tumors are unresponsive to immune checkpoint inhibitors, or therapeutical vaccines or CAR T cell-based adoptive therapy: some novel strategies to improve these T cell-based treatments are lastly proposed.

PD-1/PD-L1 blockade therapies have displayed extraordinary clinical efficacy for melanoma, renal, bladder and lung cancer; however, only a minority of colorectal cancer (CRC) patients benefit from these treatments. The efficacy of PD-1/PD-L1 blockade in CRC is limited by the complexities of tumor microenvironment. PD-1/PD-L1 blockade immunotherapy is based on T cell-centered view of tumor immunity. However, the onset and maintenance of T cell responses and the development of long-lasting memory T cells depend on innate immune responses. Acknowledging the pivotal role of innate immunity in anti-tumor immune response, this review encapsulates the employment of combinational therapies those involve PD-1/PD-L1 blockade alongside the activation of innate immunity and explores the underlying cellular mechanisms, aiming to harnessing innate immune responses to induce long-lasting tumor control for CRC patients who received PD-1/PD-L1 blockade therapy.

Clinical evidence supports the notion that T cell exhaustion and terminal differentiation pose challenges to the persistence and effectiveness of chimeric antigen receptor-T (CAR-T) cells. MEK1/2 inhibitors (MEKIs), widely used in cancer treatment due to their ability to inhibit aberrant MAPK signaling, have shown potential synergistic effects when combined with immunotherapy. However, the impact and mechanisms of MEKIs on CAR-T cells remain uncertain and controversial. To address this, we conducted a comprehensive investigation to determine whether MEKIs enhance or impair the efficacy of CAR-T cells. Our findings revealed that MEKIs attenuated CAR-T cell exhaustion and terminal differentiation induced by tonic signaling and antigen stimulation, thereby improving CAR-T cell efficacy against hematological and solid tumors. Remarkably, these effects were independent of the specific scFvs and costimulatory domains utilized in CARs. Mechanistically, analysis of bulk and single-cell transcriptional profiles demonstrates that the effect of MEK inhibition was related to diminish anabolic metabolism and downregulation of c-Fos and JunB. Additionally, the overexpression of c-Fos or JunB in CAR-T cells counteracted the effects of MEK inhibition. Furthermore, our Cut-and-Tag assay revealed that MEK inhibition downregulated the JunB-driven gene profiles associated with exhaustion, differentiation, anergy, glycolysis, and apoptosis. In summary, our research unveil the critical role of the MAPK-c-Fos-JunB axis in driving CAR-T cell exhaustion and terminal differentiation. These mechanistic insights significantly broaden the potential application of MEKIs to enhance the effectiveness of CAR-T therapy.

Ribosomal biosynthesis in nucleoli is an energy-demanding process driven by all RNA polymerases and hundreds of auxiliary proteins. We investigated how this process is regulated in activated T lymphocytes by T cell receptor (TCR) signals and the multiprotein complexes mTORC1 and mTORC2, both of which contain the kinase mTOR. Deficiency in mTORC1 slowed the proliferation of T cells, with further delays in each consecutive division, an effect not seen with deficiency in mTORC2. mTORC1 signaling was stimulated by components of conventional TCR signaling, and, reciprocally, TCR sensitivity was decreased by mTORC1 inhibition. The substantial increase in the amount of RNA per cell induced by TCR activation was reduced by 50% by deficiency in mTORC1, but not in mTORC2 or in S6 kinases 1 and 2, which are activated downstream of mTORC1. RNA-seq data showed that mTORC1 deficiency reduced the abundance of all RNA biotypes, although rRNA processing was largely intact in activated T cells. Imaging cytometry with FISH probes for nascent pre-rRNA revealed that deletion of mTORC1, but not that of mTORC2, reduced the number and expansion of nucleolar sites of active transcription. Protein translation was consequently decreased by 50% in the absence of mTORC1. Inhibiting RNA polymerase I blocked not only proliferation but also mTORC1 signaling. Our data show that TCR signaling, mTORC1 activity, and ribosomal biosynthesis in the nucleolus regulate each other during biomass production in clonally expanding T cells.

This review will explore various strategies to rendering MSS mCRCs susceptible to ICI. Moreover, we will provide an overview of potential biomarkers that may aid to better patient selection, and discuss ongoing efforts in this area of research.

Colorectal cancer (CRC) ranks among the top three most common cancers worldwide. While significant advances in treatment strategies have improved the prognosis for patients in the early stages of the disease, treatment options for metastatic CRC (mCRC) remain limited. Although immune checkpoint inhibitors (ICI) have revolutionized the treatment of several malignancies, its efficacy in mCRC is largely confined to patients exhibiting a high microsatellite instability status (MSI-H). However, the vast majority of mCRC patients do not exhibit a MSI-H, but are microsatellite stable (MSS). In these patients ICIs are largely ineffective. So far, ICIs do not play a crucial role in patients with MSS mCRC, despite the promising data for inducing long-term remissions in other tumour entities. For this reason, novel treatment strategies are needed to overcome the primary resistance upon ICI in patients with MSS.

Understanding the molecular and cellular mechanisms driving pediatric low-grade glioma (pLGG)-the most prevalent brain tumor in children-is essential for the identification and evaluation of novel effective treatments. This review explores the intricate relationship between the mitogen-activated protein kinase (MAPK) pathway, oncogene-induced senescence (OIS), the senescence-associated secretory phenotype (SASP), and the tumor microenvironment (TME), integrating these elements into a unified framework termed the MAPK/OIS/SASP/TME (MOST) axis. This integrated approach seeks to deepen our understanding of pLGG and improve therapeutic interventions by examining the MOST axis' critical influence on tumor biology and response to treatment. In this review, we assess the axis' capacity to integrate various biological processes, highlighting new targets for pLGG treatment, and the need for characterized in vitro and in vivo preclinical models recapitulating pLGG's complexity to test targets. The review underscores the need for a comprehensive strategy in pLGG research, positioning the MOST axis as a pivotal approach in understanding pLGG. This comprehensive framework will open promising avenues for patient care and guide future research towards inventive treatment options.

Combining a checkpoint inhibitor with an inhibitor of extracellular signal-regulated kinase (ERK) may result in synergistic antitumor activity. We evaluated MK-8353, an ERK1 and ERK2 inhibitor, plus pembrolizumab in a phase 1b study in patients with advanced solid tumors. This open-label, nonrandomized, dose-escalation study (NCT02972034) enrolled adults with advanced solid tumors previously treated with 1‒5 prior lines of therapy. MK-8353 was administered orally in combination with pembrolizumab 200 mg every 3 weeks as follows: twice daily (arm A; MK-8353 50‒350 mg), once daily (arm B; MK-8353 50‒600 mg), or once daily every other week (arm C; MK-8353 50‒300 mg). The primary objective was evaluation of safety via occurrence of dose-limiting toxicities (DLTs). A secondary objective was objective response by RECIST v1.1 per investigator assessment. Among 110 evaluable patients (arm A, n = 22; arm B, n = 50; arm C, n = 38), median age was 58.0 (range, 35‒79) years and 50% had received 1 or 2 prior lines of therapy. DLTs occurred in 19 patients (n = 6 [27%], n = 8 [16%], and n = 5 [13%], respectively); the most frequent was grade 3 maculopapular rash (n = 15). Grade 3/4 treatment-related AEs occurred in 35% of patients; the most common were maculopapular rash (13%) and increased lipase (5%); none were grade 5. Eight patients (7%) attained an objective response (arm B, n = 7 [complete response, n = 1; partial response, n = 6]; arm C, n = 1 [complete response]). In conclusion, MK-8353 once daily plus pembrolizumab could be administered with a manageable toxicity profile but had modest antitumor activity in patients with advanced solid tumors.

Protein kinase C α (PKCα) regulates diverse biological functions of cancer cells and is a promising therapeutic target. However, clinical trials of PKC-targeted therapies have not yielded satisfactory results. Recent studies have also indicated a tumor-suppressive role of PKCs via unclear molecular mechanisms. In this study, we found that PKCα inhibition enhances CD8+ T-cell-mediated tumor evasion and abolishes antitumor activity in immunocompetent mice. We further identified PKCα as a critical regulator of programmed cell death-ligand 1 (PD-L1) and found that it enhances T-cell-dependent antitumor immunity in breast cancer by interacting with PD-L1 and suppressing PD-L1 expression. We demonstrated that PKCα-mediated PD-L1 phosphorylation promotes PD-L1 degradation through β transducin repeat-containing protein. Notably, the efficacy of PKCα inhibitors was intensified by synergizing with anti-PD-L1 mAb therapy to boost antitumor T-cell immunity in vivo. Clinical analysis revealed that PKCα expression is positively correlated with T-cell function and the interferon-gamma signature in patients with breast cancer. This study demonstrated the antitumor capability of PKCα, identified potential therapeutic strategies to avoid tumor evasion via PKC-targeted therapies, and provided a proof of concept for targeting PKCα in combination with anti-PD-L1 mAb therapy as a potential therapeutic approach against breast cancer, especially TNBC.

MEK inhibitors (MEKi) have shown limited success as a treatment for MAPK/ERK pathway-dependent cancers due to various resistance mechanisms tumor cells can employ. CH5126766 (CKI27) is an inhibitor that binds to MEK and prevents release of RAF, reducing the relief of negative feedback commonly observed with other MEKis. We observed that CKI27 increased MHC expression in tumor cells and improved T cell-mediated killing. Yet, CKI27 also decreased T-cell proliferation, activation, and cytolytic activity by inhibiting the MAPK/ERK pathway that is activated downstream of T-cell receptor signaling. Therefore, we aimed to balance the positive and negative immunomodulatory effects of MEKis for optimal combination with immunotherapy. Intermittent administration of CKI27 allowed T cells to partially recover and costimulation via GITR and OX-40 agonist antibodies completely alleviated inhibition of function. In Kras mutant lung and colon tumor mouse models, intermittent CKI27 and anti-GITR significantly decreased tumor growth and prolonged survival when further combined with CTLA-4 immune checkpoint blockade. Moreover, this triple combination increased CD8+ and CD4+ T-cell proliferation, activation, and effector/memory subsets in the tumor-draining lymph nodes and tumors and led to intratumoral regulatory T-cell destabilization. These data, collectively, will allow for more informed decisions when optimizing combination regimens by overcoming resistance, reducing toxicity, and generating long-term immune responses.

Microsatellite stable (MSS) metastatic colorectal cancer (CRC) remains predominantly managed with chemotherapy. The use of immunotherapy, whether alone or in combination with other systemic or local treatments, displays limited success, especially in the context of active liver metastases (LM). The mechanisms responsible for this resistance are not fully understood.

We conducted a comprehensive search across electronic databases such as Medline, PubMed, Google Scholar and ScienceDirect. This search targeted translational studies evaluating the liver tumour immune microenvironment and immune tolerance mechanisms in CRC with LM and prospective studies that assessed immunotherapy either as a standalone treatment or in combination with other systemic or local therapies for patients diagnosed with MSS CRC. Our primary objectives included elucidating the mechanisms of resistance originating from LM in a non-systematic literature review and presenting a summary of the outcomes observed in prospective trials utilising immune checkpoint inhibitors (ICIs), with a focus on the presence of LM.

There were 16 prospective trials evaluating immunotherapy for metastatic CRC comprising 1,713 patients. Response rates to immunotherapy inpatients with colorectal liver metastases (CRLM) varied from 0% to 23%. Overall, reduced or null responses to immunotherapy in the presence of liver metastasis in comparison to patients without liver involvement were observed.

Studies consistently show the resistance derived from classical ICI, both alone and in combination with other systemic treatments in patients with CRLM. The design of upcoming trials using immunotherapy should consider LM as a stratification factor or contemplate excluding patients with liver involvement.

Immune checkpoint blockade with anti-programmed cell death 1 (PD-1) antibodies has demonstrated efficacy in multiple tumor types. Nofazinlimab is a humanized rat antibody targeting PD-1. A first-in-human study of nofazinlimab conducted in Australia found no dose-limiting toxicities (DLTs) and the maximum tolerated dose (MTD) was not reached in the range of 1-10 mg/kg.

We evaluated nofazinlimab for multiple advanced malignancies in Chinese patients.

This was a phase 1a/1b, open-label, multicenter, dose-escalation/expansion trial. In phase 1a, patients received an abbreviated dose escalation of nofazinlimab at 60 mg and 200 mg every 3 weeks (Q3W) to determine DLTs and the recommended phase 2 dose (RP2D). In phase 1b, patients received the RP2D (monotherapy/combination) in six arms by tumor type; DLTs were evaluated for nofazinlimab plus lenvatinib in the unresectable hepatocellular carcinoma (uHCC) arm. Safety (continuously monitored in patients who received nofazinlimab) and efficacy (patients with measurable baseline disease) were assessed.

Overall, 107 patients were eligible and received nofazinlimab. In phase 1a, no DLTs were observed; the RP2D was 200mg Q3W. In phase 1b, no DLTs were observed with nofazinlimab plus lenvatinib. The safety profile was consistent with that observed in the first-in-human study (NCT03475251). In phase 1b, 21/88 (23.9%) patients achieved confirmed objective responses, 26 (29.5%) had stable disease, and 9/20 (45.0%) patients with uHCC achieved confirmed objective responses to nofazinlimab plus lenvatinib.

Nofazinlimab was well tolerated in Chinese patients. Preliminary efficacy was encouraging, particularly for nofazinlimab plus lenvatinib in uHCC, which is being studied in an ongoing phase 3 trial.

NCT03809767; registered 18 January 2019.