Nat Commun. 2026 Jul 31;17(1):9381. doi: 10.1038/s41467-026-75949-y.

ABSTRACT

Hepatocellular carcinoma (HCC) is a cancer with high incidence and mortality rate. Although immune checkpoint inhibitors (ICIs) improved survival outcomes for HCC patients, limited objective response rate highlights the urgency of investigating determinants of immunotherapy. Here, we explore HCC resistance mechanisms following neoadjuvant αPD-1 immunotherapy by constructing a comprehensive multi-modal single-cell transcriptomic atlas consisting of 14 HCC patients treated with αPD-1 from our cohort (ClinicalTrials.gov ID: NCT06571396) and 60 external HCC cases with heterogeneous treatment backgrounds. Supervised by clinical outcomes of our cohort, we identify positive and negative regulators of immunotherapy within the tumor immune microenvironment (TIME), especially lipid-associated macrophages (LAM) with increased lipid metabolic state in non-responders and characterized by C1QA, FABP1, and APOA1 expression. We further show the presence, exogenous inducements and immunosuppressive functions of LAM, along with regulation strategies of its lipid-associated condition, including lycopene and chiglitazar. Furthermore, we construct interaction networks of immune regulators across responders and non-responders, showing distinct ligand-receptor landscapes with intervention targets. We reveal the TIME components including immunosuppressive LAMs that influence immunotherapy outcomes, thus providing evidence and insights for exploring immune landscape and therapeutic strategies for HCC immunotherapy. ClinicalTrials.gov ID: NCT06571396.

PMID:42680737 | PMC:PMC13534469 | DOI:10.1038/s41467-026-75949-y

Pharmacol Res. 2026 Apr 9:108186. doi: 10.1016/j.phrs.2026.108186. Online ahead of print.

ABSTRACT

Community-acquired pneumonia (CAP) remains a major global public health challenge with substantial morbidity and mortality. Although preclinical studies suggest that Maxing Huoqiao (MXHQ) granule may have therapeutic potential for pneumonia, high-quality clinical evidence is still limited. We conducted a multicenter, double-blind, randomized, placebo-controlled trial at two tertiary hospitals in China to evaluate the clinical efficacy of MXHQ as adjunctive therapy and to explore its potential mechanisms in adults with nonsevere CAP receiving standard moxifloxacin treatment. A total of 96 patients were enrolled and randomized (1:1:1) to receive standard-dose MXHQ, low-dose MXHQ, or placebo in addition to moxifloxacin for 7 days, with a 14-day follow-up. The primary endpoint was clinical cure, defined as composite recovery of major respiratory symptoms, lung rales, and fever; secondary endpoints included symptom relief, radiographic improvement, and safety. Compared with placebo, standard-dose MXHQ was associated with a higher day-14 clinical cure rate (30.78% vs. 68.97%; RR = 0.45, 95% CI = 0.24-0.83; P < 0.01). Furthermore, the standard-dose intervention was correlated with a shorter time to relief and recovery of cough and sputum (P < 0.05), as well as improvements in symptom scores (P < 0.05) and promoting lesion absorption on chest CT (P < 0.05). Low-dose MXHQ showed no significant clinical benefit, whereas safety profiles were comparable across all groups. Transcriptomic analyses of peripheral blood mononuclear cells, complemented by a Streptococcus pneumonia animal model, indicated that the clinical benefits of MXHQ are linked to the modulation of inflammation and innate immunity. These omics and in vivo observations suggest a potential mechanism underlying the protective effects of MXHQ against inflammatory injury and promotion of tissue repair, involving the regulation of anti-inflammatory mediators and tissue repair-related factors. (Chictr.org.cn, ID Number: ChiCTR2400082095).

PMID:41966499 | DOI:10.1016/j.phrs.2026.108186