University of San Diego

The opioid epidemic and limitations of current nonopioid analgesics have created a need for safer, effective pain therapies. Suzetrigine, a first-in-class selective NaV1.8 inhibitor, was approved by the Food and Drug Administration in 2025 for the treatment of moderate to severe acute pain. The purpose of this review is to discuss the mechanism and clinical efficacy of suzetrigine and its potential for addressing existing therapeutic gaps in pain management. Phase 3 trials have demonstrated that suzetrigine provides a statistically significant and clinically meaningful reduction in acute postoperative pain compared to placebo, with efficacy similar to hydrocodone/acetaminophen and a favorable safety profile. Mechanistic studies confirm selective peripheral NaV1.8 inhibition, minimizing central nervous system effects and abuse potential. Ongoing research is evaluating suzetrigine for chronic pain conditions including diabetic peripheral neuropathy and lumbosacral radiculopathy, though long-term efficacy and safety remain to be established. Suzetrigine represents a promising nonopioid alternative for acute pain and has the potential to fill a significant gap in pain management. While initial results are encouraging, future studies are needed to define its role in chronic pain and multimodal analgesia, and to establish long-term safety.

Autism spectrum disorder (ASD) is a highly heritable yet environmentally sensitive neurodevelopmental condition whose biological heterogeneity has resisted a unifying causal explanation for over 100 years. The 3-hit metabolic signaling model proposes that ASD arises from abnormal persistence of an evolutionarily conserved stress-response program-the cell danger response (CDR)-during critical windows of neurodevelopment. In this framework, ASD emerges from the sequential interaction of: (1) inherited genetic or epigenetic variants that sensitize mitochondrial metabolism, intracellular calcium handling, and purinergic signaling to environmental change; (2) early prenatal or postnatal activation of the CDR by infection, immune dysregulation, metabolic disturbance, or environmental toxicant exposure; and (3) prolonged or recurrent exposure to CDR-activating triggers for 3-6 months from the late 1st trimester to 18-36 months of age. The CDR is initiated by extracellular ATP (eATP)-associated purinergic signaling and mitochondrial changes that are resource- and energy-intensive. Persistent or recurrent activation of the CDR during the critical neurodevelopmental window is proposed to sensitize developing cells to eATP-related signaling, leading to false alarms and a mixture of chemical, immune, and neurosensory under- and over-responsivity. More frequent cycles of CDR activation and recovery are proposed to cause cellular competition for key bioenergetic, mitochondrial, and metabolic resources needed to support the normal trajectory of child development. Phenylketonuria (PKU) provides a proof-of-principle example. Untreated PKU historically caused intellectual disability and autistic features, while universal newborn screening and early treatment interrupt this sequence and prevent or decrease these outcomes despite strong genetic predisposition.

473 Background: KEYNOTE-564 demonstrated that adjuvant pembrolizumab improves outcomes after nephrectomy for clear-cell renal cell carcinoma (RCC). Whether this benefit extends to non–clear cell RCC (nccRCC) remains uncertain. We evaluated the association between adjuvant pembrolizumab and outcomes in patients with nccRCC who underwent nephrectomy in a multicenter study. Methods: We conducted a retrospective multicenter cohort study at six international institutions. Eligible adults had nccRCC treated with nephrectomy and were classified by receipt of adjuvant pembrolizumab. The primary endpoints were disease-free survival (DFS), defined as the time from nephrectomy to the first radiographic or clinical recurrence, and overall survival (OS), defined as the time from diagnosis to death or last follow-up. Survival functions were estimated with the Kaplan–Meier method and compared between groups using the log-rank test. Estimates of median DFS and OS were calculated using the Kaplan–Meier method. Results: Patient characteristics are shown in Table 1. Among 90 patients, 15 (17%) received adjuvant pembrolizumab, and 75 (83%) were observed; age at diagnosis was 56.0 years (IQR 44.0–63.0; mean 52.9 ± 13.1) and 62.0 years (IQR 52.0–71.0; mean 59.6 ± 14.7) respectively. Recurrence occurred in 7/15 (46.7%) with pembrolizumab and 25/75 (44.6%) with observation. There was no significant difference in median DFS (p = 0.75) or OS (p = 0.89) between groups. Median DFS was 90.7 months (95% CI, 27.2–NR) with pembrolizumab vs 41.9 months (95% CI, 39.4–NR) with observation; median OS was not reached (95% CI, 65.1–NR) with pembrolizumab vs 52.4 months (95% CI, 44.4–NR) with observation. Conclusions: In this descriptive retrospective six-center cohort of nccRCC post-nephrectomy, adjuvant pembrolizumab did not demonstrate a DFS or OS advantage over observation. A larger multi-institutional cohort is in progress to refine effect estimates using richer clinical detail, with adjusted analyses and prespecified subgroup assessment. Baseline characteristics by treatment group. Characteristic Overall (n=90) Observation (n=75) Pembrolizumab (n=15) Sex (Male/Female), n (ratio) 58 / 32 (1.8:1) 48 / 27 (1.8:1) 10 / 5 (2:1) T1, n (%) 11 (12.2%) 10 (13.3%) 1 (6.7%) T2, n (%) 10 (11.1%) 10 (13.3%) 0 (0.0%) T3, n (%) 64 (71.1%) 52 (69.3%) 12 (80.0%) T4, n (%) 3 (3.3%) 2 (2.7%) 1 (6.7%) Papillary RCC, n (%) 41 (45.6%) 36 (48.0%) 5 (33.3%) Chromophobe RCC, n (%) 31 (34.4%) 27 (36.0%) 4 (26.7%) Unclassified RCC, n (%) 7 (7.8%) 6 (8.0%) 1 (6.7%) Xp11 translocation, n (%) 8 (8.9%) 4 (5.3%) 4 (26.7%)

Myeloid-derived suppressor cells (MDSCs) are a diverse group of immature myeloid cells critically involved in establishing an immunosuppressive environment within tumors. They impede effective anti-tumor immune responses through multiple mechanisms, including metabolic reprogramming, cytokine secretion, and immune checkpoint ligand expression. This immunosuppressive activity enables tumor progression and resistance to therapies, including immunotherapy. Recent advances reveal that targeting the metabolic pathways of MDSCs can impair their suppressive functions, offering promising strategies to enhance anti-cancer immunity. Approaches such as metabolic inhibition, direct depletion, blockade of recruitment and expansion, and promotion of differentiation into mature immune cells are under active investigation. Combining these strategies with immune checkpoint inhibitors and cell-based therapies, such as cancer vaccines and adoptive T-cell or NK-cell therapies, holds significant potential for overcoming immune resistance. Nonetheless, challenges including MDSC heterogeneity, toxicity, and biomarker validation must be addressed to optimize clinical translation. This review comprehensively covers current insights into the immune-metabolic mechanisms underpinning MDSC-mediated immunosuppression in the tumor microenvironment. It explores emerging therapeutic strategies aimed at targeting MDSCs through metabolic interventions, depletion, and modulation of their recruitment and differentiation. Furthermore, it discusses the integration of MDSC-targeted approaches with existing immunotherapies, highlights ongoing clinical trials, and assesses future directions, such as personalized, biomarker-driven treatments. Ultimately, this review underscores the potential of MDSC-focused therapies to significantly improve the efficacy of cancer immunotherapy and overcome mechanisms of tumor immune evasion.

Evidence-based psychotherapies are first-line treatments for psychiatric disorders, yet response rates remain suboptimal. Noninvasive brain stimulation (NIBS) may augment psychotherapy by modulating treatment-engaged circuits. We conducted a systematic review and meta-analysis of randomized controlled trials comparing active NIBS plus evidence-based psychotherapy versus sham NIBS plus psychotherapy. Following Cochrane methods, we searched six databases through February 2025, screening 1,017 records. Twenty-eight trials (31 treatment arms; 1,506 participants) met inclusion criteria. Active NIBS combined with psychotherapy produced significantly greater symptom improvement than sham NIBS with psychotherapy (standardized mean difference = −0.38, 95% confidence interval [−0.68, −0.08]), with substantial heterogeneity. Moderator analyses revealed critical implementation parameters: repetitive transcranial magnetic stimulation (rTMS) showed significant benefit while transcranial direct current stimulation did not. Non-concurrent delivery—stimulation before or after psychotherapy sessions—was significantly effective, whereas concurrent administration was not. Among psychotherapy modalities, cognitive behavioral therapy combined with NIBS produced significant benefit. Human-delivered psychotherapy, but not computerized formats, significantly enhanced outcomes. By diagnosis, significant effects were observed only for anxiety disorders. Secondary analyses revealed significant anxiety symptom reduction specific to rTMS. Treatment integrity was under-reported: only 39.3% of studies used fully manualized protocols and 10.7% documented therapist adherence. Non-concurrent rTMS paired with human-delivered, manualized cognitive behavioral therapy emerges as the most effective strategy, particularly for anxiety disorders. These findings provide an evidence-based framework for optimizing combined treatment protocols and highlight the need for standardized psychotherapy fidelity monitoring in future trials.