Liver cancer is the third leading cause of cancer death worldwide. Hepatocellular carcinoma (HCC) is the most common primary malignant tumor of the liver. Liver resection or transplantation offer the only potentially curative options for HCC; however, many patients are not candidates for surgical resection, either due to presentation at advanced stages or poor liver function and portal hypertension. Liver transplantation is also limited to patients with certain characteristics, such as those that meet the Milan criteria (one tumor ≤ 5 cm, or up to three tumors no larger than 3 cm, along with the absence of gross vascular invasion or extrahepatic spread). Locoregional therapies, such as ablation (radiofrequency, ethanol, cryoablation, microwave), trans-arterial therapies like chemoembolization (TACE) or radioembolization (TARE), and external beam radiation therapy, have been used mainly as palliative measures with poor prognosis. Therefore, emerging novel systemic treatments, such as immunotherapy, have increasingly become popular. HCC is immunogenic, containing infiltrating tumor-specific T-cell lymphocytes and other immune cells. Immunotherapy may provide a more effective and discriminatory targeting of tumor cells through induction of a tumor-specific immune response in cancer cells and can improve post-surgical recurrence-free survival in HCC. We herein review evidence supporting different immunomodulating cell-based technology relative to cancer therapy in vaccines and targeted therapies, such as immune checkpoint inhibitors, in the management of hepatocellular carcinoma among patients with advanced disease.

In clinical organ transplantation, donor and recipient ages may differ substantially. Old donor organs accumulate senescent cells that have the capacity to induce senescence in naïve cells. We hypothesized that the engraftment of old organs may induce senescence in younger recipients, promoting age-related pathologies. When performing isogeneic cardiac transplants between age-mismatched C57BL/6 old donor (18 months) mice and young and middle-aged C57BL/6 (3- or 12- month-old) recipients , we observed augmented frequencies of senescent cells in draining lymph nodes, adipose tissue, livers, and hindlimb muscles 30 days after transplantation. These observations went along with compromised physical performance and impaired spatial learning and memory abilities. Systemic levels of the senescence-associated secretory phenotype factors, including mitochondrial DNA (mt-DNA), were elevated in recipients. Of mechanistic relevance, injections of mt-DNA phenocopied effects of age-mismatched organ transplantation on accelerating aging. Single treatment of old donor animals with senolytics prior to transplantation attenuated mt-DNA release and improved physical capacities in young recipients. Collectively, we show that transplanting older organs induces senescence in transplant recipients, resulting in compromised physical and cognitive capacities. Depleting senescent cells with senolytics, in turn, represents a promising approach to improve outcomes of older organs.

Immunosenescence, a state marked by immune dysfunction, chronic low-grade inflammation, and impaired pathogen defense, is accelerated in CKD. CKD promotes systemic inflammation through the accumulation of uremic toxins, oxidative stress, and dysregulated immune signaling, all driving premature aging of both innate and adaptive immune cells. These mechanisms result in dysregulated immune activation and impaired surveillance, thereby aggravating kidney damage and increasing the risk for comorbidities. Despite removing uremic toxins, dialysis may further accelerate immunosenescence by exposing immune cells to oxidative and antigenic stress, inducing telomere shortening and T-cell exhaustion. Kidney transplantation can partially reverse CKD-induced immunosenescence by restoring kidney function. Commonly used immunosuppressive agents, however, may further promote immunosenescence by impairing thymic function, depleting naïve T cells, and suppressing natural killer cell activity. However, mammalian target of rapamycin (mTOR) inhibitors have shown anti-aging effects by promoting autophagy and inhibiting proinflammatory pathways. Therapeutic strategies targeting immunosenescence in CKD have been gaining momentum. Senotherapeutics can eliminate senescent cells and reduce senescence-associated secretory phenotype (SASP)–mediated inflammation. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, caloric restriction, microbiome modulation, mesenchymal stem cell therapies, and KRTs also offer the potential to slow accelerated immunosenescence as a consequence of CKD. Here, we provide a comprehensive overview of the mechanisms linking CKD and immunosenescence, along with emerging therapeutic strategies that have the potential to target premature aging.

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy, and there is a need for effective systemic therapies. Gene expression profile-based analyses may allow for efficient screening of potential drug candidates to serve as novel therapeutics for patients with ICC. The RNA expression profile of ICC and normal biliary epithelial cells were downloaded from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Function annotation and enrichment pathway analyses of the differentially expressed genes (DEGs) were finished using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. A weighted gene co-expression network (WGCN) was constructed by WGCN analysis (WGCNA). Key genes from the DEGs and co-expression gene modules were analyzed to generate a protein–protein interaction (PPI) network. The association between the top 10 screened hub genes and the overall and disease-free survival of ICC patients was examined. The Connectivity Map (cMap) analysis was performed to identify possible drugs for ICC using hub genes. A total of 151 key genes were selected from the overlapping genes of 1287 GSE-DEGs, 8183 TCGA-DEGs and 1226 genes in the mixed modules. A total of 10 hub genes of interest (CTNNB1, SPP1, COL1A2, COL3A1, SMAD3, SRC, VCAN, PKLR, GART, MRPS5) were found analyzing protein–protein interaction. Using the cMap, candidate drugs screened with potential efficacy for ICC included three tyrosine kinase inhibitors (dasatinib, NVP-BHG712, tivantinib), two cannabinoid receptor agonists (palmitoylethanolamide, arachidonamide), two antibiotics (moxifloxacin, amoxicillin), one estrogen receptor agonist (levonorgestrel), one serine/threonine protein kinase inhibitor (MK-2206) and other small molecules. Key genes from network and PPI analysis allowed us to identify potential drugs for ICC. The identification of novel gene expression profiles and related drug screening may accelerate the identification of potential novel drug therapies for ICC.

Biological sex affects immunity broadly with recognized effects on incidence and severity of autoimmune diseases, infections and malignancies. Consequences of sex on alloimmunity and outcomes in solid organ transplantation are less well defined. Clinical studies have shown that donor and recipient sex independently impact transplant outcomes both, which are further modified by aging. Potential mechanisms have thus far not been detailed and may include hormonal, genetic and epigenetic components. Here, we summarize relevant findings in immunity in addition to studies in clinical and experimental organ transplantation detailing effects of biological sex on alloimmunity. Understanding both clinical impact and mechanisms is expected to provide critical insights on the complexity of alloimmune responses with the potential to fine-tune treatment and allocation while providing a rationale to include both sexes in transplant research.

Organ shortage remains a major barrier in treating end-stage organ failure, with many patients dying while waiting or becoming medically unfit by the time an organ is offered. A substantial number of organs, particularly from older donors, remain unused due to concerns over age-related decline in quality. This review highlights emerging strategies to rejuvenate and optimize such organs by mitigating ischemia-reperfusion injury and reducing age-related immunogenicity. Advances in organ preservation, perfusion technologies, and novel therapies – including senotherapeutics, anti-inflammatory agents, and stem cell treatments – show promise in improving graft viability and bridging the gap between organ supply and demand.