Cancer immunotherapy, encompassing both experimental and standard-of-care therapies, has emerged as a promising approach to harnessing the immune system for tumor suppression. Experimental strategies, including novel immunotherapies and preclinical models, are actively being explored, while established treatments, such as immune checkpoint inhibitors (ICIs), are widely implemented in clinical settings. This comprehensive review examines the historical evolution, underlying mechanisms, and diverse strategies of cancer immunotherapy, highlighting both its clinical applications and ongoing preclinical advancements. The review delves into the essential components of anticancer immunity, including dendritic cell activation, T cell priming, and immune surveillance, while addressing the challenges posed by immune evasion mechanisms. Key immunotherapeutic strategies, such as cancer vaccines, oncolytic viruses, adoptive cell transfer, and ICIs, are discussed in detail. Additionally, the role of nanotechnology, cytokines, chemokines, and adjuvants in enhancing the precision and efficacy of immunotherapies were explored. Combination therapies, particularly those integrating immunotherapy with radiotherapy or chemotherapy, exhibit synergistic potential but necessitate careful management to reduce side effects. Emerging factors influencing immunotherapy outcomes, including tumor heterogeneity, gut microbiota composition, and genomic and epigenetic modifications, are also examined. Furthermore, the molecular mechanisms underlying immune evasion and therapeutic resistance are analyzed, with a focus on the contributions of noncoding RNAs and epigenetic alterations, along with innovative intervention strategies. This review emphasizes recent preclinical and clinical advancements, with particular attention to biomarker-driven approaches aimed at optimizing patient prognosis. Challenges such as immunotherapy-related toxicity, limited efficacy in solid tumors, and production constraints are highlighted as critical areas for future research. Advancements in personalized therapies and novel delivery systems are proposed as avenues to enhance treatment effectiveness and accessibility. By incorporating insights from multiple disciplines, this review aims to deepen the understanding and application of cancer immunotherapy, ultimately fostering more effective and widely accessible therapeutic solutions. • Various aspects of immunotherapy, from its historical evolution to modern strategies and clinical applications, are explored. • Immunotherapeutic approaches, including cancer vaccines and oncolytic virus therapy, are discussed. • The efficacy and mechanisms of immune checkpoint inhibitors and adoptive cell therapies are evaluated. • The complexities of the tumor microenvironment and mechanisms of immune evasion are highlighted. • Advances in cytokines, chemokines, nanotechnology, and combination therapies that enhance immunotherapy effectiveness are outlined. • What are the primary strategies and modalities employed in cancer immunotherapy? • How does the tumor microenvironment influence the efficacy of cancer immunotherapy? • What are the key challenges in developing effective cancer vaccines and adoptive cell therapies? • How do molecular and genetic factors, including noncoding RNAs and epigenetic modifications, contribute to immunotherapy resistance? • What are the future directions for enhancing the efficacy and accessibility of cancer immunotherapy?

Overcoming therapy resistance in triple-negative breast cancer (TNBC) requires the effective targeting of cancer stem-like cells (CSCs). TNBC is characterized by hyperactivation of the mevalonate pathway, leading to cholesterol accumulation in CSC membranes, which alters membrane properties, enhances stemness, and restricts both drug penetration and lipid peroxidation-a key driver of ferroptosis. Here, we develop Fe/CDP, a nanoparticle with a Fe3O4 core coated with chondroitin sulfate and loaded with pravastatin, a mevalonate pathway inhibitor, and doxorubicin (DOX). In TNBC mouse models, Fe/CDP selectively targets tumors and CSCs via CD44-chondroitin sulfate interactions, enabling localized drug release. Pravastatin suppresses cholesterol biosynthesis, restoring membrane rigidity and fluidity, thereby reducing CSC stemness, disrupting P-glycoprotein function, and downregulating ALDH1, which enhances DOX sensitivity via the EGFR/Src/HMGCR axis. Moreover, cholesterol depletion facilitates lipid peroxidation, synergizing with Fe3O4 to trigger ferroptosis through CoQ10/GPX4/FSP1 downregulation. By eliminating both bulk tumor cells and CSCs, Fe/CDP provides a cholesterol-modulating strategy to overcome TNBC drug resistance.

Aerobic glycolysis supports tumor growth, but how tumor cells sense glucose to coordinate biosynthesis remains largely unclear. Here we show that in hepatocellular carcinoma cells, glucose-activated PKCε phosphorylates the purine synthesis enzyme ADSL, triggering its translocation to the endoplasmic reticulum. ADSL then promotes succination of INSIG1/2, which disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi, the activation of SREBP-1 and the transcription of downstream lipogenesis-related genes, proliferation of tumor cells, and tumorigenesis in mice. Through virtual screening, we identify Elsulfavirine, an approved HIV drug, which blocks ADSL-INSIG interaction and suppresses SREBP-1 activation induced by glucose. Combining Elsulfavirine with Lenvatinib synergistically inhibits tumor growth. Clinically, ADSL phosphorylation and INSIG succination correlate with SREBP-1 activation and poor prognosis in human HCC. In summary, these findings reveal a repurposing mechanism by which tumor cells coordinate glucose metabolism and lipogenesis via a moonlighting function of ADSL and underscore a repurposing strategy for liver cancer therapy.