As the most powerful professional antigen-presenting cell, dendritic cells (DCs), can effectively activate tumor-specific cytotoxic T lymphocyte responses through antigen cross-presentation (XPT), which involves endosome escape and subsequent degradation by ubiquitin-proteasome system of the exogenous tumor antigen in cytosol. Unfortunately, this important function is often compromised in the tumor microenvironment.

Optimizing T cell activation strength is emerging as a critical factor in improving adoptive cellular therapy (ACT). We previously reported that neoantigen-specific T cell receptor (TCR) clonotypes from a patient with metastatic melanoma exhibited enhanced resilience to repeated stimulation when initially activated at moderate levels.

Adoptive cell transfer-based immunotherapy holds promise for treating advanced cancer. However, a key challenge remains: generating sufficient numbers of lymphocytes capable of recognizing and targeting a broad range of cancer antigens. We recently developed Autologous Lymphoid Effector Cells Specific Against Tumor (ALECSAT), a novel procedure for selecting, expanding and maturing polyclonal lymphocytes from peripheral blood with the capacity to target cancer cells. In this single-center phase Ib trial, we evaluated the safety, tolerability, and preliminary efficacy of ALECSAT in combination with standard carboplatin and gemcitabine in patients with locally advanced or metastatic triple-negative breast cancer (mTNBC).

Aging impairs antitumor immunity and may reduce the efficacy of immune checkpoint inhibitors (ICIs). However, the underlying mechanisms remain unclear. Building on our recent findings, we review three key mechanisms of CD8 T-cell aging: elevated T-cell receptor (TCR) activation thresholds, mitochondrial dysfunction, and disruption of proteostasis. Studies in aged mice have revealed that aged naïve T cells exhibit defective priming due to increased CD45 expression, which raises the TCR activation threshold and restricts effector differentiation. Aging also impairs mitochondrial metabolism, particularly fatty acid oxidation. Furthermore, we highlight the role of proteostasis collapse, including defective autophagy and increased endoplasmic reticulum stress, as a contributor to T-cell dysfunction. Spermidine, a polyamine that declines with age, has the potential to modulate both mitochondrial function and proteostasis. Its supplementation has been shown to improve programmed cell death-1 blockade responsiveness in aged mice. Although clinical studies in humans have yielded inconsistent results regarding the effect of chronological age on ICI efficacy, identifying patients with "age-related" immune microenvironments may enable stratified therapeutic approaches based on insights from preclinical aging models.

Programmed cell death protein-1 (PD-1) blockade has shown promising clinical efficacy in hepatocellular carcinoma (HCC), yet the underlying immunological mechanisms governing response and resistance remain unclear. This study aimed to delineate the temporal and spatial dynamics of T-cell clonotypes and their relationship with pathological response in neoadjuvant PD-1 blockade therapy in HCC. By integrating T-cell receptor (TCR) repertoire analysis with transcriptomic profiling, we sought to elucidate the immune landscape alterations associated with treatment outcomes.

Cutaneous squamous cell carcinoma (cSCC) is the second most common form of skin cancer in Asian, Caucasian, and Hispanic populations and its aggressive form contributes to significant morbidity and mortality. Chronic ultraviolet B (UVB) exposure is a major environmental carcinogen that drives cSCC initiation, progression, and immune evasion. Regulatory T cells (Tregs) are known mediators of UVB-induced immunosuppression; however, their direct involvement in the establishment of cSCC remains elusive.

Blinatumomab, inotuzumab or autologous anti-CD19 chimeric antigen receptor (CAR)-T cells have revolutionized the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, tumor escape through antigenic modulation accounts for almost 40% of subsequent relapses. Multi-antigen targeting strategies should be developed, and it is urgent to identify new targets.

Common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1) is a multifunctional scavenger receptor expressed on tumor-associated macrophages (TAMs). In a recent study published in the , Yu reported that CLEVER-1 TAMs accumulate in advanced gastric cancer (GC), associate with poor prognosis, and contribute to resistance to chemoimmunotherapy. CLEVER-1 blockade using bexmarilimab reprogrammed TAMs toward a pro-inflammatory phenotype by suppressing peroxisome proliferator-activated receptor gamma (PPARγ)-driven lipid metabolism and enhancing antigen presentation and inflammatory cytokine secretion. CLEVER-1 blockade also synergized with anti-programmed cell death protein 1 (PD-1) therapy in ex vivo GC models, particularly in tumors enriched with CLEVER-1 TAM. These findings identify CLEVER-1 TAMs as both biomarker and functional mediator of anti-PD-1 therapy resistance, providing a rationale for combining bexmarilimab with immune checkpoint blockade in GC. In this commentary, we discuss the mechanistic significance, translational potential, and clinical prospects of CLEVER-1 blockade to overcome immunotherapy resistance in GC.

T-cell exhaustion induced by the tumor microenvironment is an important factor in posing a major challenge to effective cancer immunotherapy. Immune checkpoint inhibitors aim to reverse T-cell exhaustion. However, the effectiveness of immune checkpoint inhibitors is often limited due to their off-target effects and single targets. Herein, we attempt to identify molecular targets that can regulate the expression of multiple immune checkpoints to reverse T-cell exhaustion.

Predictive biomarkers for anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) therapy are needed. Here, we validated the role of PD-1 single nucleotide polymorphisms (SNPs) in predicting the development of immune-related adverse events (irAEs) in patients with advanced cancer treated with anti-PD-1/PD-L1-based immunotherapy and defined the molecular mechanisms underlying the role of identified SNP candidate.

Genetically modified cell-based therapies hold transformative potential, particularly for patients with rare cancers and ultra-rare diseases. However, progress toward regulatory approval, reimbursement, and broad patient access is often constrained by misaligned regulatory, manufacturing, and financial frameworks that do not reflect the realities of treating small populations and low-throughput production models. Drawing on a collaborative white paper and public meeting convened by Friends of Cancer Research and the Parker Institute for Cancer Immunotherapy in May 2025, this commentary outlines three strategies to streamline regulatory pathways and enable timely, sustainable access: (1) flexible approaches to Chemistry, Manufacturing, and Controls requirements in small populations, (2) adaptable regulatory frameworks to support diverse manufacturing models, and (3) limited cost recovery mechanisms to bridge early access and development gaps. Recent regulatory and policy discussions have echoed these priorities, signaling an opportunity to align oversight with operational realities to advance innovation and access for patients in high-need settings.

Enhancing immunogenicity and antigen-presentation efficiency is critical for tumor vaccine development. While yeast-surface glycoprotein side chains can improve antigen presentation, their ability to deliver tumor antigens remains limited.

Challenges to developing immunotherapies for acute myeloid leukemia (AML) include the identification of suitable target antigens due to on-target-off-leukemia toxicity. CD70, expressed on AML bulk and leukemic stem cells with limited expression on healthy cells, has emerged as a promising target.

Intrahepatic cholangiocarcinoma (ICC) offers limited opportunities for surgical treatment, and advanced-stage patients exhibit poor responses to immunotherapy. Therefore, the exploration of new therapeutic strategies is of paramount importance. The farnesoid X receptor (FXR) is a nuclear receptor that has been reported to regulate immune cells in recent years. However, whether FXR can regulate CD8 T cells to affect tumor development remains unknown.

Brain metastases (BrM) in non-small cell lung cancer (NSCLC) present a significant challenge due to poor prognosis. While immune checkpoint inhibitors (ICIs) have been standard treatments for NSCLC, their efficacy in BrM is variable, emphasizing the urgent need for predictive biomarkers and fundamental mechanisms.

Tumor-draining lymph nodes (TDLN) play a key role in inducing and promoting antitumor immunity. TDLN are commonly situated near the primary tumor and are therefore often exposed to therapeutic radiation. The impact of induction therapies comprising concurrent immunotherapy and radiation on TDLN is poorly understood. We studied the immune-modulating effects in TDLN of patients with T3-4N0-2 non-small cell lung cancer (NSCLC) using a combination of spatial transcriptomics and immunohistochemical analyses.

Immune checkpoint inhibitors (ICIs), particularly anti-PD-(L)1s, have transformed cancer care by their extended efficacy, even receiving next-line. Event-free survival 2 (EFS2), progression/recurrence-free survival 2 (PRFS2) and progression-free survival 2 (PFS2) capture the time from randomization to objective recurrence/progression or death on the first subsequent therapy, potentially offering a more accurate measure of durable benefit than first-event endpoints. Our aim is to review the magnitude of this benefit and evaluate long-term endpoints as surrogates for overall survival (OS) in immunotherapy for solid malignancies.

Immune checkpoint blockade (ICB) therapy, while transformative in cancer treatment, is frequently complicated by immune-related colitis (irColitis), driven by poorly understood mechanisms.

While chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for certain hematologic malignancies, therapeutic resistance and disease relapse highlight the critical need to improve the durability of clinical responses. The limited in vivo persistence and antitumor efficacy of CAR-T cells remain major barriers to achieving sustained therapeutic outcomes. Although CD5 has been extensively studied as a therapeutic target in cancers, particularly T-cell malignancies, its role as an immunomodulatory molecule in T cell-based immunotherapy remains poorly understood. Here, we developed a CD5-deficient T cell-based immunotherapy using the CRISPR-Cas9 system to address these limitations and enhance antitumor potency.

Personalized cancer vaccines targeting tumor-specific neoantigens (nAgs) are an emerging therapeutic strategy, particularly effective in early-stage disease before immune suppression is established. Immune checkpoint inhibitors have demonstrated benefit in the adjuvant setting (postsurgery), and recent evidence suggests neoadjuvant administration (before surgery) may further enhance antitumor immunity. This study evaluated the efficacy of a multiepitope nAg vaccine in a preclinical melanoma model resistant to checkpoint inhibition, comparing neoadjuvant and adjuvant treatment, alone or in combination with anti-programmed cell death protein 1 (PD1) therapy.

Immunity to solid tumors is associated with the hallmarks of cancer-associated inflammation and the ability of immune mechanisms to limit tumor progression. Application of expanded tumor-infiltrating lymphocyte adoptive T cell therapy (TIL ACT) in clinical trials is now practiced at many sites around the world. Prior to immune checkpoint blockade (ICB), an approximate 50% objective response rate was consistently observed across multiple institutions for patients with melanoma. This now-approved strategy approaches 35% in recent studies from the USA and 49% with more highly selected patients in Europe. Here, we focus on early TIL studies in non-melanoma epithelial neoplasms. Increased understanding of cancer immunology has allowed changes in the TIL expansion process to include: (1) initial generation of TIL from fragments, (2) use of specialized large-scale culture vessels, (3) use of the rapid expansion protocol to enable 'young' TIL prosecution, and (4) treatment regimens employing non-myeloablative (NMA) chemotherapy followed by brief interleukin-2 administration. NMA leads to homeostatic proliferation of the transferred T cells, engraftment, profound neutropenia and lymphopenia, and improved clinical outcome. A key success of TIL ACT relies on the quality, specificity, and number of pre-existing TIL. This, in turn, is highly influenced by the suppressive tumor microenvironment. Thus, any means to alter 'cold tumor (non-T cell inflamed)' to 'hot tumor (T cell inflamed)' is theoretically desirable to improve both the quality and quantity of TIL obtained before harvest. Combinations of other immunotherapies such as application of ICB, co-stimulatory molecule agonist antibodies, autophagy inhibition, and dendritic cell support strategies could provide additional- improvements in TIL therapy and enable harnessing of the adaptive immune response to enhance the clinical outcome of TIL-ACT patients.