Hepatocellular carcinoma (HCC) is the deadliest emergent health issue around the globe. The stronger oncogenic effect, proteins, and weakened immune response are precisely linked with a significant prospect of developing HCC. Several conventional systemic therapies, antiangiogenic therapy, and immunotherapy techniques have significantly improved the outcomes for early-, intermediate-, and advanced-stage HCC patients, giving new hope for effective HCC management and prolonged survival rates. Innovative therapeutic approaches beyond conventional treatments have altered the landscape of managing HCC, particularly focusing on targeted therapies and immunotherapies. The advancement in HCC treatment suggested by the Food and Drug Administration is multidimensional treatment options, including multikinase inhibitors (sorafenib, lenvatinib, regorafenib, ramucirumab, and cabozantinib) and immune checkpoint inhibitors (atezolizumab, pembrolizumab, durvalumab, tremelimumab, ipilimumab, and nivolumab), in monotherapy and in combination therapy to increase life expectancy of HCC patients. This review highlights the efficacy of multikinase inhibitors and immune checkpoint inhibitors in monotherapy and combination therapy through the analysis of phase II, and III clinical trials, targeting the key molecular pathways involved in cellular signaling and immune response for the prospective treatment of advanced and unresectable HCC and discusses the upcoming combinations of immune checkpoint inhibitors-tyrosine kinase inhibitors and immune checkpoint inhibitors-vascular endothelial growth factor inhibitors. Finally, the hidden challenges with pharmacological therapy for HCC, feasible solutions for the future, and implications of possible presumptions to develop drugs for HCC treatment are reported.

Hepatocellular carcinoma (HCC) is the most common liver cancer, with poor survival rates in advanced stages due to late diagnosis, tumor heterogeneity, and therapy resistance. The tumor microenvironment (TME) in HCC has a crucial role in tumor progression, characterized by a complex interaction of immune cells, stromal components, and immunosuppressive signaling pathways. Chronic inflammation driven by viral infections, metabolic dysfunction, and alcohol consumption triggers an immunosuppressive TME, promoting immune evasion and tumor growth. Immune cell populations, such as myeloid-derived suppressor cells, regulatory T cells, and tumor-associated macrophages, contribute to immunosuppression, while cytotoxic T lymphocytes and natural killer cells exert anti-tumor effects. Recent advances in immunotherapy, mainly immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 and programmed cell death protein 1 and cytotoxic T-lymphocyte-associated protein 4, have revolutionized HCC treatment, though response rates remain limited. Combined therapies using tyrosine kinase inhibitors, anti-angiogenic agents, and ICIs improve patient outcomes. This review discusses the immunological mechanisms contributing to HCC progression, the role of immune cell subsets in tumor evasion, and therapeutic interventions, from conventional treatments to advanced immunotherapies. Ongoing clinical trials, barriers to effective treatment, and future directions to enhance HCC management and patient survival will also be overviewed.

Dengue virus infection is a serious public health concern all over the world including Pakistan. Currently, there is no effective treatment to control dengue infection. So, there is a dire need to identify safe and low cost drug against dengue virus. This study was planned to computationally screen the phytochemicals of C. papaya against dengue NS2B/NS3 serine protease which is essential and specific for the virus replication. For this purpose, a library of 900 bioactive compounds were screened against NS2B/NS3 to find out potential candidates against dengue NS2B/NS3. Nine compounds (1-Hydroxy-2-propanone, 2-methyl-propanoic acid, baicalein, 2-methyl-butanoic acid, epigallocatchin, fisetin, genistein, catechin and protocatechuric acid) out of 900 were ranked on the basis of S-score (-5.7626, -6.8558, -7.2808, -6.4986, -7.5166, -13.1129, -7.5972, -9.0272, -7.3422 and rmsd value 0-9580, 1.5403, 2.1917, 1.9903, 2.9203, 3.4554, 2.4394, 3.1414 and 1.8594) and high bonding interaction with NS2B/NS3 serine protease. The screened compounds were further filtered through ADMET profiling and Lipinski’s rule of five. Three compounds: Epigallocatchin, catechin and protocatechuric acid having interaction with active residues His51, Asp75, Ser135 were predicted. The analysis shows potential of phytochemicals from C. papaya for possible anti-dengue agent in pharmaceutical as well as nutraceutical industry.