Triple Negative Breast Cancer

P1, N=96, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Apr 2026 --> Apr 2028 | Trial primary completion date: Apr 2026 --> Apr 2028

P2, N=46, Active, not recruiting, Virginia Commonwealth University | Trial completion date: Mar 2026 --> Mar 2027

P2, N=80, Recruiting, Sun Yat-sen University | Not yet recruiting --> Recruiting

P2, N=6, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Trial completion date: Apr 2026 --> Nov 2025

Second-generation clocks demonstrated stronger prognostic signal than first-generation models in unadjusted analyses. Among them, GrimAge1 retained independent prognostic value beyond established clinicopathologic factors in breast cancer, supporting further external validation with richer covariates to refine clinical utility.

Functional perturbation studies further indicated that EGFR, TNFα, and TNFAIP3 contribute to PTOX-induced macrophage clearance. Together, these findings identify PTOX as a novel phagocytosis-sensitizing agent and support its potential as a combinatorial immunotherapeutic strategy to enhance CD47-targeted therapy in TNBC.

Compared with GR-low disease, treatment-naïve GR-high primary TNBC exhibits a more immunosuppressive tumor microenvironment characterized by greater Treg density, closer Treg-cancer cell proximity, reduced NK cell infiltration, impaired immune surveillance, and decreased abundance of HLA-ABC+ cancer cells. These findings implicate TNBC cell GR signaling as immunosuppressive, likely through mechanisms resulting in both differential immune cell enrichment and altered spatial organization.

Docetaxel and vadimezan (DMXAA), a prototypical STING agonist, were co-loaded into GO-EDM to generate GO-EDM-DTX-Vad. Taken together, GO-EDM-DTX-Vad leverages passive tumor accumulation and mannose receptor-guided dual targeting of TAMs and TIDCs to integrate DTX-based chemotherapy, STING-mediated immune activation and mild NIR photothermal therapy. This integrated chemo-photothermal-immunotherapeutic design couples direct tumor cell killing with myeloid reprogramming and immune activation, offering a unified strategy for metastatic TNBC.

In the murine TNBC model, EMMDs demonstrated remarkable antitumor efficacy, obviously provoking a robust STING-mediated type I interferon response and inhibiting tumor growth. This work presents a promising biomimetic strategy for remodeling the tumor immune microenvironment via efficient STING activation.

FA-PEG@ZIF8@CIP was constructed as a folic acid-polyethylene glycol-functionalized ZIF8 nanoplatform for the delivery of ciprofloxacin...This multifunctional nanosystem enables the integration of diagnosis and therapy and represents a promising strategy for TNBC treatment. By combining targeted delivery, pH-responsive drug release, ultrasound imaging, and synergistic therapeutic effects within a single platform, FA-PEG@ZIF8@CIP may offer a valuable approach for improving theranostic outcomes in TNBC.

A central thesis of this review is that these six contextual determinants establish a framework for understanding receptor pleiotropy. Furthermore, while targeting Plexin-B signaling shows therapeutic promise (eg, pepinemab in clinical trials), indiscriminate inhibition risks abrogating tumor-suppressive functions and perturbing immune microenvironment homeostasis, underscoring the necessity for biomarker-driven stratification to prevent paradoxical oncogenic consequences.

Our findings reveal intricate interactions among immune cell composition, GZMK expression, senescence, and TNBC, highlighting GZMK as a potential molecular target for therapeutic intervention. This study advances the understanding of TNBC pathogenesis and opens new avenues for precision medicine in TNBC treatment.