Kymera Therapeutics

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterised by synovial inflammation and joint destruction, in which fibroblast-like synoviocytes (FLS) play a pivotal role through their hyperproliferative, invasive and inflammatory properties. The salt-inducible kinase (SIK) family regulates inflammatory responses, yet the role of its isoform SIK3 in RA and the therapeutic potential of its inhibition remain unclear. This study investigates the effects of HG-9-91-01, a potent SIK inhibitor, on RA-FLS pathogenicity and disease progression. The impact of HG-9-91-01 on human MH7A cells was assessed using cell counting kit-8, 5-ethynyl-2'-deoxyuridine, flow cytometry, wound healing and Transwell assays. RNA sequencing, bioinformatics analyses and western blot analysis were employed to explore the underlying mechanisms. The therapeutic efficacy of HG-9-91-01 was evaluated in a murine collagen-induced arthritis (CIA) model through clinical scoring, histopathology and micro-CT imaging. SIK3 was significantly upregulated in RA synovial tissues and correlated with disease activity. HG-9-91-01 potently inhibited MH7A cell proliferation, migration and invasion while promoting apoptosis. Transcriptomic and molecular analyses revealed that these effects were mediated through the concurrent suppression of the phosphoinositide 3-kinase-protein kinase B (PI3K-Akt) and nuclear factor kappa B (NF-κB) signalling pathways, leading to downstream modulation of Bcl-2-associated X protein, B-cell lymphoma 2, inducible nitric oxide synthase, tumour necrosis factor-α and matrix metalloproteinase-9. In CIA mice, HG-9-91-01 administration markedly alleviated arthritis severity, synovitis, cartilage degradation and bone erosion. Our findings demonstrate that HG-9-91-01 attenuates RA progression by directly targeting FLS pathogenicity via dual inhibition of PI3K-Akt and NF-κB signalling, highlighting the therapeutic potential of SIK family inhibition in RA.

Combinatorial immunotherapies have revolutionized the clinical management of advanced malignancies, yet their prominent anti-tumor efficacy is frequently compromised by treatment-induced skeletal muscle dysfunction governed by reciprocal signaling circuitry bridging the tumor microenvironment (TME) and peripheral muscle compartments. This review systematically delineates conserved soluble mediator and cytokine networks underlying therapy-triggered myotoxicity across five core combinatorial regimens, chemoimmunotherapy, targeted immunotherapy, gene therapy, tumor vaccines, and CAR-T cell therapy, alongside modality-specific toxic signaling axes. Cancer-associated fibroblast-derived TGF-β, glycolysis-originated lactate, and IL-6/TNF-α-centered inflammatory cascades converge to activate the myostatin/FoxO3 transcriptional program and ubiquitin-proteasome proteolysis, disrupting muscle anabolic-catabolic homeostasis. Type II fast-twitch glycolytic fibers and muscle satellite cells display disproportionate susceptibility to inflammatory and metabolic damage, whereas clinical confounders including corticosteroid exposure, chronological age, and sex hormones stratify interpatient vulnerability to muscle wasting. Conventional and emerging skeletal muscle biomechanical assessment modalities are critically benchmarked, with electrical impedance myography highlighted as a high-sensitivity platform for subclinical tissue remodeling detection, and tiered multimodal monitoring pipelines are formulated for prospective immunotherapy clinical trials. Translational muscle-protective interventions covering structured resistance training, personalized nutritional supplementation, and anti-cachexia pharmacotherapy are comprehensively consolidated. Collectively, this review establishes an integrated mechanistic and translational framework to advance holistic oncologic care that reconciles robust anti-tumor immunity with sustained skeletal muscle integrity.

Background: Although cancer immunotherapies have revolutionized cancer treatment, a substantial proportion of patients remain unresponsive. Elucidating the molecular mechanisms underlying tumor immune evasion and identifying key regulators are essential for improving immunotherapy efficacy. NOP2/Sun RNA methyltransferase 2 (NSUN2) exhibits widespread mutations across pan-cancer cohorts. This study aimed to delineate the noncanonical functions of NSUN2 in cancer immune modulation and explore its potential as a therapeutic target for cancer immunotherapy. Methods: Multiple cancer cells expressing catalytically inactive NSUN2 mutants were generated and subjected to in vitro functional assays and in vivo studies in immunocompetent mouse models to evaluate their effects on tumor growth and antitumor immunity. Integrative multi-omics analyses, including transcriptomics, metabolomics, and mass spectrometry, were performed to elucidate the molecular mechanisms underlying NSUN2-mediated immune evasion. A proteolysis-targeting chimera (PROTAC) system was developed to achieve targeted degradation of NSUN2, and the clinical relevance of NSUN2 expression in predicting immunotherapy responses was assessed using institutional and public datasets. Results: The enzymatically inactive NSUN2 mutant had minimal effects on tumor cell proliferation in vitro but markedly promoted tumor immune evasion in vivo. Multi-omics analyses revealed that NSUN2 induced metabolic reprogramming and elevated succinate levels, which suppressed cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signaling in tumor-associated macrophages (TAMs), thereby remodeling the tumor immune microenvironment and promoting M2-like TAM infiltration. Mechanistically, NSUN2 interacted with GATA-binding protein 3 (GATA3) through its methyltransferase domain, relieving GATA3-mediated transcriptional repression of succinate-CoA ligase GDP/ADP-forming subunit α and β genes (SUCLG1 and SUCLG2), leading to succinate accumulation. A newly developed NSUN2-targeting PROTAC demonstrated therapeutic efficacy and safety in combination with cancer immunotherapy. Clinically, low NSUN2 expression was associated with improved immunotherapy responses and survival. Conclusions: Taken together, these findings revealed a noncanonical role of NSUN2 in reshaping the tumor immunosuppressive microenvironment, positioning NSUN2 as a pivotal repressor of cancer immunity and a promising immunotherapeutic target.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a significant pathogen in the swine industry that causes reproductive failure in sows and respiratory distress in pigs of all ages, leading to substantial economic losses globally. PRRSV manipulates host cellular processes, particularly those associated with endoplasmic reticulum (ER) function. ER-phagy plays a crucial role in maintaining ER homeostasis and enabling cellular adaptations to stress. Whether and how PRRSV modulates ER-phagy remains incompletely understood. ER-phagy was monitored by western blotting for free mCherry from the mCherry-Sec61B reporter. FAM134B mRNA and protein levels were examined by RT-qPCR and western blotting, respectively. All 12 PRRSV Nsps were screened for FAM134B-suppressing activity by co-transfection, followed by western blotting. Co-immunoprecipitation (Co-IP) was performed to assess interactions between candidate Nsps and FAM134B, as well as their impact on FAM134B- microtubule-associated proteins light chain 3 (LC3) binding. Viral replication was evaluated by RT-qPCR targeting ORF7 and TCID50 assays. We investigated the interplay between PRRSV and ER-phagy and discovered that PRRSV suppresses ER-phagy during the late stages of infection. Further analysis revealed that PRRSV employs its Nsps to inhibit the expression of FAM134B. Specifically, PRRSV Nsp2 and Nsp5 interact with FAM134B, promote its degradation and disrupt its binding to microtubule-LC3, thereby impairing ER-phagy. Collectively, our findings uncover a novel viral strategy to subvert host ER-phagy and provide new insights into PRRSV pathogenesis.

Immune-mediated inflammatory diseases (IMIDs) refer to a heterogeneous group of conditions driven by dysregulated immune responses that affect multiple organs and systems, leading to substantial morbidity and premature mortality. Accumulating evidence indicates that excessive interleukin-6 (IL-6) production and aberrant activation of downstream signaling pathways play central roles in sustaining chronic inflammation and acute hyperinflammatory states. This review aims to summarize the current understanding of IL-6 biology and signaling modes, and critically evaluate therapeutic strategies targeting IL-6 across multiple IMIDs. We discuss the clinical efficacy and limitations of approved IL-6 signaling inhibitors in chronic immune-mediated disorders and acute systemic inflammation, as well as emerging evidence supporting pathway-selective interventions such as IL-6 trans-signaling blockade. In addition, recent advances in therapeutic innovation, including proteolysis-targeting chimeras, clustered regularly interspaced short palindromic repeats (CRISPR)-based genome engineering, RNA interference, and nanotechnology-enabled drug delivery platforms, are highlighted for their potential to improve specificity, tissue targeting, and durability of IL-6 modulation. In summary, these developments reflect a shift from uniform cytokine inhibition toward more selective and physiologically informed approaches, which may ultimately refine IL-6 targeted therapies and improve outcomes across diverse IMIDs.

Microbial cell therapies hold considerable promise as programmable and versatile modalities for targeted interventions in complex biological environments. Here, we developed a living bacterial delivery platform that could leverage its endogenous metabolism to synchronize the release of surface-anchored targeted protein degradation (TPD) chimeras and the secretion of immune-modulatory nanobodies (Nbs) for enhanced antitumor efficacy. By means of metabolic labeling coupled with bioorthogonal click chemistry, transferrin (Tf)-CD24 antibody chimeras (TransCACs) were covalently displayed on the surface of nonpathogenic Escherichia coli (E. coli) K12. In parallel, this strain was equipped with a constitutive expression module for the in situ biosynthesis of PD-L1-blocking nanobodies. Capitalizing on the natural tumor tropism of bacteria, our engineered E. coli K12 achieved tumor-targeted CD24 degradation, thereby augmenting macrophage-mediated phagocytosis and synergizing with PD-L1 blockade to elicit robust tumor-specific CD8+ T cell immunity. In vivo administration of engineered microbes led to marked tumor growth inhibition in both subcutaneous breast and orthotopic hepatocellular carcinoma models, along with prolonged animal survival, driven by remodeling of the suppressive tumor microenvironment through coordinated crosstalk between M1-like macrophages and tumor-resident memory (TRM)-like CD8+ T cells. Altogether, this integrated genetic engineering and metabolic labeling of bacteria (InGeM) opens avenues for the development of next-generation microbe-based cancer immunotherapies.

The development of proteolysis-targeting chimeras (PROTACs) represents a promising strategy for targeted protein degradation in cancer therapy. However, the limited tumor-specific targeting and the inherent unfavorable physicochemical properties of PROTACs lead to insufficient cellular uptake and suboptimal antitumor immune responses. Herein, as a proof of concept, we developed an oncolytic virus-PROTAC conjugate (BPAD) by efficiently coupling bromodomain-containing protein 4 (BRD4)-targeting PROTACs with oncolytic viruses (OVs). In BPAD, the potent and highly selective infection of OVs to tumor cells enhances both cellular uptake and tumor-selective delivery of PROTACs, resulting in a 640-fold increase in the protein degradation efficiency. Moreover, prior to OV-induced tumor lysis, the preferential replication of OVs within tumor cells, combined with BRD4 degradation, promotes the secretion of type I interferons and facilitates dendritic cell maturation. Overall, the BPAD strategy enables the development of biologically derived macromolecular PROTAC conjugates, thereby enhancing the clinical translation potential of diverse PROTACs.