The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53’s tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53 but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53’s functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment.

The Murine Double Minute 2 (MDM2) gene encodes an E3 ubiquitin ligase that negatively regulates the tumor suppressor p53, maintaining low p53 levels through ubiquitination and proteasomal degradation. MDM2 overexpression in various malignancies leads to reduced p53 activity, contributing to tumor initiation and resistance to therapies. As such, MDM2 is a promising target for drug development. Innovative small-molecule inhibitors are being designed to disrupt the MDM2-p53 interaction, thereby restoring p53’s tumor-suppressive functions. This review focuses on clinical trials evaluating MDM2 inhibition for cancer therapy. MDM2 exerts its oncogenic effects primarily through its interaction with p53, but also has p53-independent functions involved in cell cycle progression and DNA repair. Elevated MDM2 expression is associated with poor prognosis across various cancers, including dedifferentiated liposarcoma, breast cancer, and glioblastoma. Targeting MDM2 with inhibitors has shown promising potential in clinical development, aiming to reactivate p53’s functions in tumors with wild-type TP53, improving therapeutic outcomes in cancer treatment.

Photodynamic therapy (PDT) remains constrained by physical barriers, including strict oxygen dependence, acute hypoxia exacerbation, and limited light penetration depth. While conventional photodynamic therapy (PDT) is strictly oxygen-dependent and limited by light scattering, Near-Infrared Photoimmunotherapy (NIR-PIT) overcomes microenvironmental hypoxia through targeted, oxygen-independent biophysical membrane rupture. However, tissue optical attenuation at 690 nm remains a fundamental physical boundary that necessitates interstitial fiber placement for deep lesions. Concurrently, recent advances in bioengineered nano-photoimmunotherapy (nano-PIT) and organelle-targeted photodynamic/photothermal platforms deliberately execute alternative inflammatory non-apoptotic pathways, such as pyroptosis, cuproptosis, and ferroptosis, and provoke cytosolic leakage of mitochondrial DNA that engages the cGAS-STING innate immune axis. Concurrently, NIR-PIT comprehensively remodels the immunosuppressive tumor microenvironment (TME) by selectively depleting regulatory T cells (Tregs), myeloid-derived suppressor (MDSCs) cells, and cancer-associated fibroblasts (CAFs), thereby deconstructing desmoplastic stroma, lowering interstitial fluid pressure (IFP), and driving the Super-Enhanced Permeability and Retention (SUPR) effect. Photically released mitochondrial DNA further engages the cytosolic cGAS-STING pathway, stimulating type I interferon signaling and dendritic cell cross-presentation. In selected preclinical models, this biophysical collapse promotes immunogenic cell death (ICD) and tumor microenvironment remodeling. When combined with systemic immunotherapies, NIR-PIT has demonstrated the potential to prime antitumor immunity and elicit abscopal responses in responsive syngeneic models; however, this immune conversion is not universal and is heavily constrained by tumor mutational burden, baseline antigen presentation fidelity, and diverse immunosuppressive networks. Translating these paradigms into clinical practice requires advancing 3D microphysiological models, implantable light technologies, and multi-component dosimetry frameworks.

Cutaneous melanoma is an aggressive skin cancer. While laser therapy is established for non-melanoma skin cancers, its role in melanoma remains controversial and largely unsupported by robust clinical evidence. The gold standard for melanoma management remains surgical excision, as it allows for definitive histopathological diagnosis, Breslow thickness measurement, and surgical margin assessment, which are essential for accurate staging. This narrative review analyzed preclinical and clinical studies evaluating various laser modalities, including Nd:YAG, CO₂, pulsed dye, photodynamic therapy (PDT) and photothermal therapy (PTT), for efficacy, recurrence rates, and limitations in cutaneous melanoma management. Nd:YAG laser (1064 nm) showed potential for local control in thin stage I melanomas, reporting a low local recurrence rate of 0–0.7% and favorable 5-year survival in small, non-randomized cohorts. CO₂ laser (10,600 nm) provides effective palliation and local control for in-transit or unresectable metastases, but local recurrence is highly variable, reaching up to 46.7%. Photodynamic therapy showed variable efficacy, although Chlorin e6 achieved complete local regression in a small series of metastases. A critical limitation of laser therapy is the irreversible destruction of tissue, which precludes these vital assessments. Therefore, laser treatment should be cautiously reserved for cases where standard surgery is not feasible, acknowledging that it may interfere with the evaluation of curative outcomes and accurate staging. Laser therapy is a valuable minimally invasive adjunct for local control in selected patients who are poor surgical candidates or require palliative care. Routine use is restricted by the lack of randomized controlled trials. Future studies should prioritize combination strategies with systemic or immunotherapeutic approaches to enhance overall outcomes.