Kymera Therapeutics

Musculoskeletal dysfunction and compromised physical performance are prevalent complications observed in individuals diagnosed with cancer, frequently intensified by the administration of chemotherapy, radiotherapy, and extended periods of physical inactivity. Polyphenols (bioactive constituents derived from various plant sources) have exhibited significant anti-inflammatory, antioxidant, and anti-apoptotic characteristics that may serve to augment exercise interventions aimed at improving musculoskeletal recovery and rehabilitation outcomes. This review encapsulates the existing preclinical and clinical evidence regarding the synergistic effects of polyphenol supplementation in conjunction with structured exercise protocols in the context of cancer, with particular emphasis on underlying molecular mechanisms and functional outcomes. Prominent signaling pathways influenced by these combined therapeutic strategies include Wnt/β-catenin, PI3K/Akt, TNF-α/NF-κB, IL-4/STAT6, and TGF-β1/TRAF6, which are integral to the regulation of inflammation, apoptosis, muscle metabolism, and tissue remodeling. Preclinical investigations conducted using rodent cancer models consistently reveal that polyphenols such as curcumin, resveratrol, and genistein, significantly enhance the efficacy of both aerobic and resistance exercise concerning tumor suppression, muscle preservation, and modulation of molecular pathways. Clinical evidence, although scarce, suggests potential enhancements in muscular strength, endurance, and recovery when polyphenolic compounds are utilized in conjunction with exercise rehabilitation, particularly among individuals undergoing oncological treatment. Despite these encouraging results, variability in dosing regimens, formulations, timing, and participant demographics constrains the generalizability of the findings. Subsequent research endeavors should prioritize the development of standardized polyphenolic preparations, refined exercise protocols, and clinically relevant functional outcomes to establish evidence-based clinical guidelines. The integration of polyphenols with exercise represents an auspicious non-pharmacological approach to augment musculoskeletal function and enhance quality of life in the context of cancer rehabilitation.

Resistance to combination regimens containing the B-cell lymphoma 2 (BCL-2) inhibitor and BH3 mimetic venetoclax in acute myeloid leukemia (AML) is a growing clinical challenge for this extensively used agent. We previously established the antileukemic properties of ceramide, a tumor-suppressive sphingolipid, in AML, and demonstrated that upregulated expression of acid ceramidase (AC), a ceramide-neutralizing enzyme, supports leukemic survival and resistance to BH3 mimetics. Here, we report the antileukemic efficacy and mechanisms of cotargeting AC and BCL-2 in venetoclax-resistant AML. Analysis of the BeatAML data set revealed a positive relationship between increased AC gene expression and venetoclax resistance. Pharmacologic AC inhibition with the ceramide analog SACLAC enhanced single-agent venetoclax cytotoxicity and the venetoclax + cytarabine combination in AML cell lines with primary or acquired venetoclax resistance. SACLAC + venetoclax was synergistically lethal when evaluated ex vivo across a cohort of venetoclax-resistant (n = 21) and venetoclax-sensitive (n = 46) primary samples from patients with AML. Moreover, the SACLAC + venetoclax combination was equipotent to the combination of venetoclax + cytarabine at reducing cell viability across primary patient samples. Mechanistically, cotargeting AC and BCL-2 increased ceramide to levels that trigger a cytotoxic integrated stress response (ISR), ISR-mediated NOXA protein upregulation, mitochondrial dysregulation, and caspase-dependent cell death. Importantly, AC knockdown sensitized AML cells to venetoclax and induced NOXA protein accumulation, whereas NOXA knockdown protected against AC and BCL-2 cotargeting. Collectively, these findings demonstrate the efficacy of cotargeting AC and BCL-2, and rationalize targeting AC as a therapeutic approach for venetoclax-sensitive and -resistant AML.

Modulating the cGAS-STING pathway by bioactive nanodevices is a promising strategy for combating infection-associated inflammatory disorders. However, the development of pharmacological inhibitors for cGAS-STING signaling is currently hindered by lacking cell-specific targeting capability. This study aimed to develop a potent, drug-free nanodevice that specifically targets pulmonary macrophages to modulate the cGAS-STING pathway for ameliorating infection-associated detrimental lung inflammation. Cigarette smoke extract-modified peptide gold nanoparticle hybrids (CSE-P12) were synthesized. Transcriptomic analysis, western blotting, autophagy reporter assays, and confocal microscopy were employed to assess the effects of CSE-P12 on gene expression, STING degradation, autophagic flux, and inflammation. TEM imaging and LC-MS/MS were utilized to elucidate the molecular mechanisms underlying CSE-P12-induced autophagy in macrophages. Finally, the HAdV4-induced pneumonia and CLP-induced sepsis models on wild-type and STING-/- mice were used to evaluate the therapeutic efficacy of CSE-P12 and validate its inhibitory mechanisms on the cGAS-STING pathway. CSE-P12 nanodevices are extensively internalized by macrophages via energy-dependent cellular uptake. This large internalization triggers autophagic degradation of STING, thereby effectively inhibiting the cGAS-STING-mediated interferon responses and inflammation. In the HAdV4-induced viral pneumonia mouse model, intratracheally instilled CSE-P12 effectively targets pulmonary macrophages, suppresses STING activation, and significantly alleviates lung inflammation and injury. The depletion of the pulmonary macrophages abolishes these protective effects. The therapeutic potential of CSE-P12 is further validated in a CLP-induced polymicrobial sepsis mouse model, where it significantly prolongs mouse survival and decreases lung inflammation. CSE-P12 effectively targets pulmonary macrophages and exhibits potent anti-inflammatory activities in viral pneumonia and sepsis-induced acute lung injury by inducing autophagic flux to facilitate STING degradation. This work provides a new paradigm for designing targeted nanotherapeutics to modulate STING activation in inflammatory diseases.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease that affects physical, social and emotional aspects of life for people living with HS (plwHS). Although many plwHS consider pain the most bothersome symptom, fatigue and sleep disturbance are underexplored in research and rarely discussed in clinical practice. This article shares perspectives from plwHS and people working with patients, including healthcare professionals (HCPs), from Europe and North America, on the impact of HS-related fatigue and sleep disturbance on quality of life (QoL). Fatigue was described as a debilitating symptom affecting QoL, with HCPs often noting that plwHS were unaware of the full impact of fatigue until treatment improved their HS symptoms. Sleep disturbance was mainly attributed to HS-related pain, pruritus and lesion drainage, with sleep deficits accumulating over time. The strain of HS impacted personal relationships, with plwHS expressing less interest in social interactions or intimate relationships, leading to feelings of guilt, failure, isolation and reduced self-esteem. Fatigue and sleep disturbance also affected work productivity, and consequently, career progression and financial stability. Recognizing the multifaceted HS symptoms, providing reasonable adjustments in the workplace, encouraging open dialogue with HCPs and measuring fatigue with a validated instrument could help improve QoL of plwHS.

Glutaminyl-peptide cyclotransferase (QPCT, QC) and its isoenzyme glutaminyl-peptide cyclotransferase-like protein (QPCTL, isoQC) are zinc-dependent enzymes that post-translationally catalyze the conversion of N-terminal glutamine or glutamate residues into pyroglutamate (pGlu). The pGlu modification impacts protein-protein interactions, enhances protein stability, and protects proteins from proteolytic degradation. QPCTL and QPCT differ in their subcellular localization, with QPCTL being retained in the Golgi apparatus and QPCT being active in secretory vesicles. Current research focuses on the impact of QPCTL-mediated pGlu formation in cancer and neurodegenerative disorders such as Alzheimer's disease. In cancer, QPCTL is a promising immunotherapy target since QPCTL-mediated CD47 pyroglutamylation prevents macrophages from phagocytosing tumor cells. Moreover, QPCTL shapes the tumor microenvironment by modulating macrophage recruitment and polarization through modification of CCL2. However, QPCTL modulates Butyrophilins on tumor cells and thereby promote their detection and killing by γδ T cells. Hence, QPCTL significantly affects cancer progression, inflammatory processes, and immune regulation. These insights highlight QPCTL's potential as a therapeutic target in oncology, metabolic diseases, and immune-mediated disorders. In this review, we highlight the role of QPCTL in tumor evasion and immune modulation. Moreover, we provide a comprehensive overview about predicted and validated substrates of QPCT/L and about the relevance of QPCT/L in various diseases.

Cancer immunotherapy has revolutionized cancer treatment, yet its effects extend far beyond tumor eradication. Accumulating evidence indicates that immunotherapy-associated skeletal muscle dysfunction represents a complex, cross-organ pathological process driven by dynamic crosstalk between the tumor microenvironment and peripheral tissues. Rather than an isolated adverse event, muscle injury emerges from integrated mechanisms including inflammatory cytokine spillover, aberrant immune cell infiltration, metabolic reprogramming, vascular dysfunction, and impaired regenerative signaling. Central to this process is the sustained activation of the NF-κB and JAK/STAT3 axes, which links systemic immune activation to ubiquitin-proteasome-mediated proteolysis, mitochondrial dysfunction, and suppression of anabolic pathways. Meanwhile, metabolic coupling between tumor glycolysis and skeletal muscle energetics establishes a bidirectional feedback loop that exacerbates catabolism and compromises antitumor immunity. Clinically, baseline sarcopenia and therapy-induced myotoxicity reciprocally impair immunotherapeutic efficacy, forming a self-reinforcing cycle that limits treatment continuity and long-term survival. Advances in multimodal imaging, including PET/CT, shear wave elastography, and dynamic contrast-enhanced MRI, combined with artificial intelligence-driven quantitative analysis, provide a noninvasive framework to decode metabolic, mechanical, and vascular signatures of muscle vulnerability. Emerging interventions targeting inflammatory signaling, metabolic imbalance, vascular dysregulation, and regenerative pathways offer promising strategies to dissociate antitumor efficacy from systemic toxicity. Future research should prioritize longitudinal, multi-omics-integrated, and imaging-guided approaches to clarify causal hierarchies and enable precision risk stratification. Bridging mechanistic insight with perioperative and translational strategies will be essential to achieving comprehensive cancer care in the immunotherapy era.

Infectious spleen and kidney necrosis virus (ISKNV) induces aerobic glycolysis, leading to lactate accumulation. Lysine lactylation is a novel post-translational modification that employs lactate as its substrate. However, its landscape and functions during ISKNV infection remain elusive. In this study, we explored lactylation modification and lactylome in Chinese perch brain (CPB) cells after ISKNV infection. Results showed that the total lactylation level was significantly downregulated at 60 h post-infection (hpi), even though lactate was upregulated. Lactylome analysis identified 527 differentially lactylated proteins (DLPs) at 60 hpi, corresponding to 233 up-regulated and 456 down-regulated sites. The two particularly preferred sequence motifs of upregulated and downregulated lactylation were L*Kla and K/G***Kla***P, respectively. Functional enrichment analysis demonstrated that the up-regulated lactylated proteins were significantly enriched in spliceosome, nucleocytoplasmic transport, ribosome, and glycolysis pathways. Down-regulated lactylated proteins were abundant in ferroptosis, Wnt signaling pathway and lysine degradation. Network analysis of lactylated proteins demonstrated that the lactylation of ALDH-mt-like Iso X1, VDAC2, VDAC2-like Iso X1, VDAC1, and DVL3-like were linked to glycolysis, ferroptosis, necroptosis, and Notch signaling pathway. The downregulation of VDAC2 lactylation and upregulation of VDAC1, ALDH2 induced by ISKNV were verified by Co-IP, which confirmed the reliability of the lactylome data. These results showed that protein lactylation played a functionally significant regulatory role in metabolism and immunity during ISKNV infection, offering novel mechanistic insights and promising targets for ISKNV.