Immunotherapy has revolutionized the landscape of cancer treatment, yet its efficacy is often limited by drug resistance, the immunosuppressive tumor microenvironment (TME), and the "undruggable" nature of key immunoregulatory proteins. Targeted protein degradation (TPD) technology, which harnesses cellular degradation machinery to eliminate disease-associated proteins, is emerging as a transformative strategy in the field of tumor immunotherapy. This review systematically summarizes recent advances in various TPD strategies-based on both the ubiquitin-proteasome system (UPS) and the lysosomal pathway, such as proteolysis-targeting chimera (PROTAC), molecular glues, lysosome-targeting chimera (LYTAC), and antibody-based PROTAC (AbTAC)-within the context of cancer immunotherapy. We emphasize how TPD molecules can directly degrade key target proteins, including immune checkpoints, to alleviate immunosuppression, as well as clear critical immunomodulatory factors within the TME, thereby synergistically reversing immunosuppression and enhancing antitumor immunity. Furthermore, this article discusses the rational design, preclinical validation, and clinical translation trends of TPD-based immunotherapeutic agents. Despite encouraging progress, challenges such as tissue selectivity, off-target effects, and delivery efficiency remain to be addressed. Finally, we envision future directions for advancing the application of TPD technology in cancer immunotherapy.

Mitochondria, the powerhouse of the cell, orchestrate a plethora of critical functions, including energy production, metabolic regulation, programmed cell death, and signal transduction. Their pivotal role in the pathogenesis of numerous diseases underscores their significance. Among the various regulatory mechanisms, RNA modifications emerge as a dominant posttranscriptional modulator of gene expression, increasingly recognized for their profound impact on mitochondrial functions. Groundbreaking discoveries have unveiled compelling links between RNA modifications and oxidative phosphorylation, regulated cell death-particularly cuproptosis-and antitumor immunity, underscoring RNA modifications' vital role and untapped potential in mitochondrial biology, cancers and aging-related diseases. In this Review, we comprehensively catalog the primary RNA modifications modifiers and their small-molecule inhibitors that influence mitochondrial functions. We explore the latest research delineating RNA modifications' involvement in mitochondria-related glucose metabolism, regulated cell death, and mitochondrial dynamics, presenting an intricate regulatory network. Furthermore, we investigate the intriguing intersection of RNA modifications and mitochondria-related antitumor immunity, highlighting prospective therapeutic targets to enhance immunotherapy outcomes. This review not only accentuates the critical importance of RNA modifications in mitochondrial function but also paves the way for novel therapeutic strategies in disease treatment.

Consolidation durvalumab following no progression on concurrent chemoradiotherapy (cCRT) is standard of care for unresectable stage III non-small-cell lung cancer (NSCLC). However, in clinical practice many patients receive sequential CRT (sCRT). The PACIFIC-5 trial aimed to evaluate the efficacy and safety of consolidation durvalumab for unresectable stage III NSCLC following no progression on cCRT or sCRT.

Bacterial therapy represents a promising strategy for cancer treatment, in which tumor regression can be achieved through bacteria-mediated immunotherapy. The mechanisms involve disrupting cellular metabolism, inducing apoptosis, delivering therapeutic agents, and enhancing anticancer immune responses. Naturally occurring bacteria possess inherent advantages in biocompatibility and self-propulsion. Facultative anaerobic species, such as Salmonella, can increase tumor accumulation by more than tenfold through the enhanced permeability and retention (EPR) effect. However, the application of native bacterial therapy is limited by its toxicity and unstable colonization in vivo at disease sites. The negatively charged bacterial surface and abundant functional groups enable surface modifications through ionic interactions or covalent bonding. These approaches include modifying lipopolysaccharides and capsules that trigger in vivo toxicity, or coating bacteria with exogenous nanomaterials to achieve detoxification and construct drug delivery platforms. Furthermore, gene editing and synthetic genetic circuit strategies allow the precise engineering of bacteria to improve tumor targeting, reduce pathogenicity, and endow them with novel anticancer functions. This review discusses the routes of bacterial administration, surface engineering strategies, synthetic circuit design, and clinical translation in bacteria-mediated cancer immunotherapy. It comprehensively summarizes the historical progress, advantages, and distinctive features of bacterial therapy, with a particular emphasis on recent advances in synthetic gene circuit design. Finally, the review highlights the clinical translation prospects and existing challenges of bacteria-mediated tumor therapy, aiming to ensure biosafety, prevent unintended immune responses, and promote large-scale clinical applications in cancer treatment.

B-cell maturation antigen (BCMA)-targeted positron emission tomography/computed tomography (PET/CT) represents a promising tool for the management of multiple myeloma, enabling noninvasive and quantitative evaluation across different disease stages. This novel technique specifically addresses two major diagnostic challenges: the limited specificity of conventional F-FDG PET/CT and the focal sampling constraints of bone marrow biopsies. In this prospective study, a Ga-labeled nanobody-based BCMA tracer demonstrated improved detection compared with F-FDG PET/CT, effectively visualizing para-medullary, extra-medullary and medullary lesions, as well as minimal residual disease (MRD). The tracer also reflected dynamic changes in BCMA expression associated with treatment response, underscoring its potential utility for guiding BCMA-targeted interventions, particularly in the era of chimeric antigen receptor T-cell (CAR-T) treatment. These preliminary findings support the potential of BCMA immunoPET as a comprehensive, noninvasive modality for MM evaluation and warrant validation in larger, prospective clinical trials.

Olutasidenib is an oral, selective inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1), FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML) based on a registrational, phase 2, open-label, multicenter trial.

Chimeric antigen receptor T-cell (CAR-T) therapy has demonstrated a transformative impact in hematologic malignancies and offers a promising strategy to offer new hope for patients with solid tumors who have failed multiple lines of treatment. The clinical application of CAR-T therapy in solid tumors, however, still has challenges, including tumor heterogeneity, an immunosuppressive tumor microenvironment, and safety concerns. These hurdles have mean that CAR-T therapy has become both a focal point and a pivotal trend in contemporary clinical research. The American Society of Clinical Oncology (ASCO) Annual Meeting serves as a premier venue for unveiling groundbreaking clinical data. In this review, we highlight the main phase I clinical trial advances in CAR-T therapy for solid tumors presented at the 2025 ASCO Meeting.

Chimeric antigen receptor T cell (CAR-T) therapy has emerged as a highly efficacious treatment for refractory and relapsed hematological malignancies in recent years. However, the complex manufacturing procedures, stringent logistical requirements, and protracted production timelines associated with autologous ex vivo CAR-T cells render them costly and inaccessible to many patients. In contrast, in vivo CAR-T therapy directly delivers CAR-encoding transgenes to endogenous T cells, reprogramming them in situ. This approach obviates the need for apheresis, ex vivo cell manufacturing, and lymphodepleting chemotherapy inherent in conventional CAR-T therapy. Consequently, in vivo CAR-T represents a more efficient and economical paradigm, transforming CAR-T from individualized cellular products towards truly "ready-to-use" therapeutics. This review summarizes the latest research progress in in vivo CAR cell therapies, spanning from bench to bedside, to provide insights for advancing their clinical translation.

Tertiary lymphoid structures (TLSs) are ectopic lymphoid aggregates that form in or in close proximity to tumors and other chronically inflamed tissues, where they serve as crucial sites for local antigen presentation, lymphocyte priming, and adaptive immune coordination. Increasing evidence across diverse cancers supports TLSs as key modulators of antitumor immunity, correlating with improved patient prognosis and response to immune checkpoint blockade. Yet, TLSs exhibit striking spatiotemporal and functional heterogeneity-ranging from immune-stimulatory to immune-suppressive-which complicates their clinical interpretation and therapeutic targeting. Recent studies have focused on elucidating the molecular cues driving TLS induction, the mechanisms regulating their maturation, and their dynamic interactions with the tumor microenvironment. In this review, we provide an integrated overview of these advances and discuss the clinical and translational implications of TLSs as prognostic biomarkers and immunotherapeutic targets.

Small molecule inhibition of BCL-XL with navitoclax resulted in on-target dose-limiting thrombocytopenia. DT2216 was more effective than navitoclax and reduced platelet toxicity in preclinical models by selectively degrading BCL-XL via the VHL E3 ligase, which is minimally expressed in platelets.

Cancer immunotherapy originated from the use of Coley's toxins at the end of the nineteenth century. However, immunotherapy had not made great strides in cancer treatment until the discovery of immune checkpoints among which cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed cell death 1 (PD-1), and programmed cell death ligand 1 (PD-L1) are the most representative ones. Since the first CTLA-4 inhibitor ipilimumab started the first clinical trial in 2000, immune checkpoint inhibitor (ICI) therapy has gradually emerged as the most successful and widely applied strategy in the field of cancer immunotherapy, revolutionizing treatment paradigms across a broad spectrum of malignancies. Recently, the approvals of monoclonal antibodies targeting lymphocyte activation gene-3 (LAG-3) and novel bispecific antibodies targeting immune checkpoints may indicate the next wave of ICI agents development in cancer immunotherapy. In this review, we aimed to provide a comprehensive overview and in-depth discussion covering the current ICI treatment landscape in the past 26 years (2000-2025), indications and limitations of efficacy-predicting biomarkers, immune-related adverse events, resistance mechanisms and overcoming strategies, as well as future directions of ICI therapy.

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and 2 (12%) had R/R B-ALL; 9 (53%) had a KMT2A-r but none had an NPM1 mutation. The median prior lines of therapy was 3 (range 1-8) and 5 patients (29%) had received prior menin inhibitors. Five dose escalation cohorts were evaluated; no RP2D was established, and the trial was stopped at phase 1 due to a decision by supporting company due to lack of efficacy at studied dose levels and portfolio realignment. Differentiation syndrome (DS) was seen in 5 patients (29%); 2 in cohort 1 (70 mg twice daily, n = 4) 1 each had grade 1 and grade 4 DS, 3 patients in cohort 2 (50 mg twice daily/100 mg daily, n = 4) of whom 2 had grade 2 and 1 patient had grade 3 DS (considered as dose limiting toxicity). No DS was noted at cohort 3 (20 mg/day), and in subsequent dose-escalation cohorts (cohorts 4 and 5) a lead-in ramp-up dosing starting at 20 mg/day was instituted to improve tolerability. Other relevant treatment emergent adverse events of grade ≥ 3 included infections; pneumonia and febrile neutropenia in 7 patients each (41%), and sepsis in 6 patients (35%). No study drug related deaths were noted. No patient achieved a response, however 4 patients (23%) had > 25% bone marrow blast reduction. Pharmacokinetic analysis showed DS-1594b reached maximum concentration approximately in 2 h with total exposure increasing with escalating doses and reached stead-state by Cycle 1 Day 8. DS-1594b showed limited efficacy at the doses tested but appeared safe with a lead-in dosing approach.

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated substantial efficacy against various hematological malignancies. The remarkable success of CAR-T cell therapy in targeting B-cell malignancies has generated significant interest in its potential application for treating autoimmune diseases (ADs). By engineering T cells to express CARs that specifically recognize B-cell antigens, researchers aim to selectively eliminate or modulate the dysregulated autoimmune responses underlying disease pathology. Early clinical trials targeting the B-cell marker CD19 have shown promising results, including clinical remission in patients with B-cell-mediated ADs. To broaden therapeutic potential and improve the safety profile of CAR-T cell therapy in autoimmunity, innovative strategies are under investigation. These include the development of chimeric autoantibody receptors (CAARs) for the precise depletion of autoantigen-specific B cells, and the engineering of regulatory T cells (Tregs) expressing antigen-specific CARs to achieve targeted immune modulation. Critical considerations for the safe and effective translation of CAR-T therapy to ADs include optimal target cell identification, CAR construct design, toxicity management, and the capacity to induce durable immune tolerance. This review explores strategies to optimize CAR-T cell therapies for ADs, focusing on enhancing efficacy and addressing current limitations. We summarize recent advances in alternative cell sources, CAR structural modifications, genetic and metabolic interventions, clinical translation, and the integration of novel technologies, presenting approaches poised to improve the efficacy and applicability of CAR-T cell therapy in ADs.

CAR T cell therapy targeting BCMA has shown remarkable efficacy in multiple myeloma (MM), but relapses occur due to T cell exhaustion and the emergence of BCMA-negative subpopulations. Novel targets are needed to overcome antigen escape.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by desmoplastic stroma, immunosuppressive tumor microenvironment (TME), and resistance to standard therapies. Natural killer (NK) cell-based immunotherapies have shown limited efficacy due to impaired persistence, infiltration, and function in PDAC.

Concerns have emerged regarding the oncogenic potential of glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter 2 (SGLT2) inhibitors, particularly in relation to gynecologic malignancies. To date, no consensus has been reached on regimen-specific risks. This network meta-analysis (NMA) evaluated and compared the incidence of gynecologic tumors associated with various GLP-1 receptor agonists and SGLT2 inhibitors.

Interleukin-1 receptor accessory protein (IL1RAP) is selectively expressed on both bulk blasts and leukemic stem cells (LSCs) in acute myeloid leukemia (AML), while its expression is virtually absent on normal hematopoietic stem cells (HSCs), making it an appealing target for chimeric antigen receptor (CAR) T cell therapy.

With high-risk neuroblastoma, post-induction metastases in bone marrow (BM)/bones confers a poor prognosis but can respond to anti-G antibody, such as naxitamab. We report results of a phase I/II trial.

Antibody-drug conjugates (ADCs) have revolutionized cancer therapy, but therapeutic resistance poses a significant barrier to sustained efficacy. Multiple mechanisms contribute to ADCs resistance, including drug efflux mediated by transporters, alterations in target antigens, tumor heterogeneity, and the impact of the tumor microenvironment (TME). Clinically, ADCs resistance varies across different cancer types, treatment lines, and patient subgroups. Emerging strategies now emphasize precision targeting through bispecific ADCs, alongside advancements in linker chemistry, payload design, and TME modulation. Additionally, rational combination therapies have emerged as a promising approach to reverse ADCs resistance, demonstrating synergistic effects. This review summarizes current understanding of mechanisms driving ADCs resistance and recent advances in combination therapies. By integrating mechanistic insights with emerging strategies, we aim to provide a comprehensive framework for addressing ADCs resistance and propose future research directions. These efforts may improve the efficacy of ADCs and the outcomes of cancer patients.

Inflammasomes are being increasingly recognized for their critical roles in regulating immune cell infiltration, antitumor immunity, and tumorigenesis in cancer biology. The expression and activation of inflammasomes, which vary according to the tumor type and stage, influence both tumor progression and elimination through pyroptosis. A deeper understanding of the complex functions and regulatory mechanisms of inflammasomes and pyroptosis in diverse aspects of tumor biology is crucial for the development of targeted therapies. In this review, we extensively explore the latest research on various types of inflammasomes, including NOD-like receptor family pyrin domain-containing 3 protein, NOD-like receptor family caspase recruitment domain-containing protein 4, and absent in melanoma 2, and different types of pyroptosis, highlighting their beneficial and deleterious effects on various cancers. We further explore inflammasome-associated immune dynamics, which can drive either tumor suppression or promotion depending on the microenvironmental context. Finally, we discuss emerging strategies to harness inflammasomes for cancer therapy, along with ongoing clinical efforts to develop inflammasome-targeted interventions as adjuncts to conventional antitumor treatments, offering new perspectives for cancer prevention and therapy.