Cancer cells express high levels of programmed cell death-ligand 1 (PD-L1) to evade immune surveillance. PD-L1 interacts with PD-1 on T cells to make them non-functional. Thus, PD-L1 and PD-1 are pivotal targets in cancer immunotherapy. While anti-PD-1/PD-L1 therapies have offered renewed hope for many patients, their modest efficacy remains a critical concern. This underscores the urgent need to unravel the intricate mechanisms that govern both therapeutic responses as well as resistance to immunotherapy. This review explores the multifaceted nature of PD-L1, including factors that regulate its expression, tumor-immune interactions, and the resistance mechanisms associated with anti-PD-L1 immunotherapy. Several promising strategies have been explored to overcome these challenges, such as combination therapies, modulation of the tumor microenvironment, neoantigen targeting, and dynamic biomarker monitoring. Outcomes of these approaches, integrating advanced technologies like high-resolution imaging, machine learning, multi-omics profiling, and liquid biopsy for soluble PD-L1 detection emerge as a powerful means to refine patient stratification. Together, these innovations pave the way toward more precise and personalized immunotherapy, maximizing clinical benefits for cancer patients. Additionally, the evolving landscape of clinical trials involving anti-PD-1/PD-L1 monoclonal antibodies has been explored, emphasizing the integration of immune checkpoint therapies with chemotherapy, radiotherapy, targeted therapy, CAR-T, and metabolic immunotherapy to overcome resistance in refractory cancers. By embarking on these challenges and leveraging novel therapeutic strategies, this review intends to advance the understanding of more effective, personalized cancer immunotherapies, ultimately improving outcomes for a broader range of patients.

Glycoconjugates, due to their diverse functions, are widely regarded as biologically important molecules. Artemisinic acid 1 occurs naturally in the plant Artemisia annua and is considered to be the biogenetic precursor of the antimalarial drug, artemisinin 2. We report herein the design and synthesis of diverse artemisinic acid derived glycoconjugates. We have synthesized 12-O-artemisinic acid-glycoconjugates (7a–k) and 12-N-artemisinic acid-glycoconjugates (8a–k) by utilizing Cu(I)-catalyzed azide-alkyne cycloaddition reactions (Click chemistry) with various synthesized sugar azides (6a–k) in good to excellent yields along with two fluorescently labeled compounds, 12-O-artemisinic acid-glycoconjugate 11 and 12-N-artemisinic acid-glycoconjugate 12, to investigate the mode of action of these compounds in biological systems. All the synthesized artemisinic acid glycoconjugates were assayed for their efficacy against the MCF7 cell line. Our anticancer studies indicated that all the synthesized compounds inhibited the growth of MCF7 cells in a dose dependent manner, barring compounds 4 and 7d. However, these compounds exhibit moderate cytotoxicity, as is evident from their IC₅₀ values.

Oncogene Moesin plays critical role in initiation, progression, and metastasis of multiple cancers. It exerts oncogenic activity due to its high-level expression as well as posttranslational modification in cancer. However, factors responsible for its high-level expression remain elusive. In this study, we identified positive as well as negative regulators of Moesin. Our study reveals that Moesin is a cellular target of F-box protein FBXW2. We showed that FBXW2 suppresses breast cancer progression through directing proteasomal degradation of Moesin. In contrast, AKT kinase plays an important role in oncogenic function of Moesin by protecting it from FBXW2-mediated proteasomal degradation. Mechanistically, AKT phosphorylates Moesin at Thr-558 and thereby prevents its degradation by FBXW2 via weakening the association between FBXW2 and Moesin. Further, accumulated Moesin prevents FBXW2-mediated degradation of oncogene SKP2, showing that Moesin functions as an upstream regulator of oncogene SKP2. In turn, SKP2 stabilizes Moesin by directing its non-degradable form of polyubiquitination and therefore AKT-Moesin-SKP2 oncogenic axis plays crucial role in breast cancer progression. Collectively, our study reveals that FBXW2 functions as a tumor suppressor in breast cancer by restricting AKT-Moesin-SKP2 axis. Thus, AKT-Moesin-SKP2 axis may be explored for the development of therapeutics for cancer treatment.

Cell death is a fundamental process essential to all living organisms, with apoptosis serving as one of the most crucial pathways across various stages of life. Dysregulation of apoptosis is closely associated with numerous diseases, particularly cancer. PUMA (p53 upregulated modulator of apoptosis) is a key mediator of apoptotic cell death. It is activated in response to a wide range of internal and external signals. Beyond its established role in apoptosis, PUMA also regulates other forms of cell death, including necroptosis, autophagy, and ferroptosis, underscoring its critical role in cancer cell death, especially during chemotherapy. However, PUMA activation is frequently impaired in many cancers, leading to resistance to cell death and treatment failure. This review highlights recent advancements in understanding the regulation of PUMA expression at multiple levels, including epigenetic, transcriptional, post-transcriptional, and post-translational mechanisms. It also examines the influence of diverse cellular regulators, such as epigenetic modifiers, transcription factors, non-coding RNAs, kinases, and ubiquitin ligases in modulating PUMA activity. Additionally, we discuss PUMA’s role in cancer progression, its impact on the effectiveness of anti-cancer therapies, and its potential as a prognostic biomarker for therapeutic resistance. Finally, we propose critical questions to inspire future research, aiming to deepen the understanding of PUMA regulation and its significance in cancer therapy. The diagram highlights the regulatory network of p53 under stress conditions such as DNA damage, hypoxia, or oncogenic stress. In normal conditions, MDM2 binds to and sequesters p53, leading to its proteasomal degradation. Stress signals activate p53, inducing the pro-apoptotic protein PUMA, which inhibits anti-apoptotic proteins (BCL-2, BCL-XL, and BCL-W), thereby activating the effector proteins BAX and BAK. This activation results in mitochondrial outer membrane permeabilization (MOMP) and cytochrome c (Cyt c) release, triggering caspase activation and apoptosis. Proper apoptosis maintains tissue homeostasis, whereas alterations in this pathway can lead to uncontrolled cell proliferation and cancer.