Trabectedin (TRB) and Lurbinectedin (LUR) are alkaloid compounds originally isolated from Ecteinascidia turbinata with proven antitumoral activity. Both molecules are structural analogues that differ on the tetrahydroisoquinoline moiety of the C subunit in TRB, which is replaced by a tetrahydro-β-carboline in LUR. TRB is indicated for patients with relapsed ovarian cancer in combination with pegylated liposomal doxorubicin, as well as for advanced soft tissue sarcoma in adults in monotherapy. LUR was approved by the FDA in 2020 to treat metastatic small cell lung cancer. Herein, we systematically summarise the origin and structure of TRB and LUR, as well as the molecular mechanisms that they trigger to induce cell death in tumoral cells and supporting stroma cells of the tumoral microenvironment, and how these compounds regulate immune cell function and fate. Finally, the novel therapeutic venues that are currently under exploration, in combination with a plethora of different immunotherapeutic strategies or specific molecular-targeted inhibitors, are reviewed, with particular emphasis on the usage of immune checkpoint inhibitors, or other bioactive molecules that have shown synergistic effects in terms of tumour regression and ablation. These approaches intend to tackle the complexity of managing cancer patients in the context of precision medicine and the application of tailor-made strategies aiming at the reduction of undesired side effects.

The cytokine storm associated with SARS‐CoV‐2 infection is one of the most distinctive pathological signatures in COVID‐19 patients. Macrophages respond to this pro‐inflammatory challenge by reprogramming their functional and metabolic phenotypes. Interestingly, human macrophages fail to express the inducible form of the NO synthase (NOS2) in response to pro‐inflammatory activation and, therefore, NO is not synthesized by these cells. The contribution of exogenously added NO, via a chemical NO‐donor, on the immunometabolic changes associated with the cytokine storm is investigated. By using metabolic, transcriptomic, and functional assays the effect of NO in human macrophages is evaluated and found specific responses. Moreover, through integrative fluxomic analysis, pathways modified by NO that contribute to the expression of a particular phenotype in human macrophages are identified, which includes a decrease in mitochondrial respiration and TCA with a slight increase in the glycolytic flux. A significant ROS increase and preserved cell viability are observed in the presence of NO, which may ease the inflammatory response and host defense. Also, NO reverses the cytokine storm‐induced itaconate accumulation. These changes offer additional clues to understanding the potential crosstalk between NO and the COVID‐19 cytokine storm‐dependent signaling pathways.

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation and characterized by oxidative damage to membrane phospholipids. Increasing evidence indicates that ferroptosis contributes to myocardial ischemia-reperfusion injury (MIRI), a condition that worsens cardiac damage following restoration of blood flow to the ischemic myocardium. This study aimed to investigate the role of ferroptosis in MIRI and to determine whether pharmacological activation of the vitamin D receptor (VDR) by paricalcitol modulates ferroptosis-associated cardiac injury. Myocardial ischemia-reperfusion was induced in mice by transient ligation of the left anterior descending coronary artery followed by reperfusion. Cardiac function was evaluated by cardiac magnetic resonance imaging. Ferroptosis-related pathways were analyzed through transcriptional profiling of antioxidant and iron-regulating genes, lipidomic assessment of oxidized phospholipid species, and ultrastructural mitochondrial evaluation. Complementary in vitro experiments were performed using human AC16 cardiomyocyte-like cells under ferroptotic stress. Ischemia-reperfusion led to a sustained deterioration of cardiac structure and function and induced several alterations consistent with ferroptosis activation, including changes in ferroptosis-related gene expression, accumulation of oxidized phospholipid species, and mitochondrial structural abnormalities. Pharmacological activation of VDR by paricalcitol attenuated ferroptosis-related transcriptional alterations, reduced lipid peroxidation, and mitigated mitochondrial structural damage, collectively limiting ferroptosis-associated cardiomyocyte injury and early ventricular dilation and systolic dysfunction. These findings suggest that VDR activation limits ferroptosis-associated cardiac injury during myocardial ischemia-reperfusion and may represent a pharmacologically relevant strategy to mitigate cardiac damage linked to ferroptosis.

Understanding the interplay between immune and stromal cells in the tumor microenvironment is essential for developing effective cancer therapies and preventing relapses. In this review, starting with the basics of tumor immunology and a historical review from cancer chemotherapy to current immunotherapy, in the context of precision medicine, we focus on immunotherapies based on genetically modified macrophages, and chimeric T-cell antigen receptor (CAR), highlighting the similarities and differences between TCR-endogenous signaling and CART-dependent signaling at the immune synapse, presenting all the generations that have been developed briefly, followed by NK cell-dependent CAR therapeutic approaches where a comparison is established, analyzing their respective advantages and drawbacks. Targeting the tumor-immune microenvironment has become central to cancer treatment, with combinatorial therapies applied and assessed as a feasible strategy for this complex group of diverse pathologies. In this context, modulating the immune synapse, rewiring immune cell metabolism, and developing genetically engineered immune cells have emerged as promising approaches that open novel avenues for treating and managing cancer patients. This review offers a holistic, historical view of state-of-the-art molecular approaches, along with insights into future perspectives and current limitations of the technologies supporting immunotherapy in molecular oncology.