The C-X-C motif chemokine receptor 4 (CXCR4)/C-X-C motif chemokine ligand 12 (CXCL12) axis drives immune exclusion in pancreatic ductal adenocarcinoma (PDA). Building on our preclinical data, we conducted the first stage of an open-label, single-arm phase 2 clinical trial combining CXCR4 inhibition (motixafortide), PD-1 blockade (cemiplimab), and chemotherapy (gemcitabine/nab-paclitaxel [GN]; MCGN) in 11 treatment-naïve patients with metastatic PDA ( NCT04543071 ). The primary endpoint, objective response rate, was 64% partial response and 55% confirmed partial response per Response Evaluation Criteria in Solid Tumors. Secondary endpoints include median progression-free survival of 9.7 months (95% confidence interval [CI]: 5.9-not reached [NR]), overall survival of 10.1 months (95% CI: 9.3-NR), duration of response of 8.2 months, and 91% disease control rate. One patient achieved a pathological complete response after pancreatoduodenectomy and hepatectomy, remaining disease-free for 18 months without adjuvant therapy. Exploratory single-nucleus RNA-sequencing of serial biopsies showed reduced tumor heterogeneity, depletion of epithelial-to-mesenchymal transitional states, and enrichment of CXCL12+ cancer-associated fibroblasts in responders relative to resistant patients. MCGN also induced tumor inflammation as confirmed by tissue staining and T cell rescue. A multicenter randomized phase 2 trial comparing MCGN to GN in patients with treatment-naïve metastatic PDA is ongoing.

Breast cancer chemotherapy is hindered by multiple therapeutic challenges, including tumor immune evasion and ferroptosis resistance. Herein, we design and synthesize carrier-free prodrug self-assembled nanoparticles (PSSE NPs) with an ultrahigh drug-loading capacity. In response to the high intracellular glutathione (GSH) abundance in tumor cells, the disulfide bonds embedded in PSSE NPs are cleaved, enabling the simultaneous release of paclitaxel (PTX) and erianin (ERI). Specifically, PTX exerts potent chemotherapeutic efficacy against breast cancer cells, whereas ERI initiates tumor ferroptosis and facilitates immunogenic cell death (ICD). The subsequently activated CD8⁺ T cells secrete interferon-γ (IFN-γ), which downregulates SLC7A11 expression, suppresses GSH biosynthesis, and further sensitizes tumor cells to ferroptosis. In vitro experimental results confirm that PSSE NPs trigger robust ferroptosis by elevating intracellular reactive oxygen species (ROS) levels and promoting excessive lipid peroxidation (LPO) accumulation. In three distinct breast cancer animal models (subcutaneous xenograft, bilateral tumor, and lung metastasis models), PSSE NPs significantly inhibit tumor proliferation and metastasis while eliciting systemic antitumor immune responses. This study constructs a positive feedback loop of ferroptosis-immunity synergism via a prodrug nanoplatform strategy, realizing the synergistic integration of chemotherapy, ferroptosis induction, and tumor immunotherapy. This work thereby provides a feasible and high-efficiency prodrug nanotherapeutic strategy for improving breast cancer chemotherapy outcomes.

[This corrects the article DOI: 10.1016/j.mtbio.2023.100567.].

Breast cancer is the most common cancer diagnosis in women. Clinical studies with triple-negative breast cancer (TNBC) are encouraging for immunotherapy combined with chemotherapy (anti-PD-1 with paclitaxel and/or carboplatin). However, additional clinical advances may be pursued more rapidly with assistance from preclinical TNBC models including syngeneic mammary tumor cell lines. Here, we report two mammary tumor cell lines that exhibit differential responsiveness to immunotherapy in vivo. Spontaneous mammary tumors from C57BL/6J MMTV-Cre Trp53fl/+ animals were passaged serially in cell culture and in vivo in the mammary fat pad of fully wildtype animals. The resulting lines, MM001i and MM008i, lost Trp53 and formed 1000 mm3 tumors in the mammary fat pad within 21-28 days. Despite originating from the same genetic background, these lines exhibit differential responses to immunotherapy. For anti-PD-1 therapy, MM001i is poorly responsive and MM008i is strongly responsive with near-complete tumor regression. In comparison, both MM001i and MM008i respond rapidly to anti-CTLA-4 therapy. Both models express unique tumor antigens as evidenced by immunity to subsequent engraftments. Primary MM008i tumors exhibit greater T cell infiltration, and CD8-positive T lymphocytes are required for anti-PD-1 responses. These TNBC models are promising for further mechanistic studies and testing future single and combinatorial therapies.

Microwave ablation (MWA) is an effective locoregional therapy for solid tumors, but recurrence caused by minimal residual disease remains a clinical challenge. Although immunotherapy offers a strategy to prevent recurrence, the role of tumor-draining lymph nodes (TDLNs) in post-ablation immune regulation remains underexplored. Here, single-cell RNA sequencing (scRNA-seq) reveals pronounced macrophage remodeling in TDLNs following incomplete MWA (iMWA), characterized by an increased representation of immunosuppressive Folr2[+] and Apoe[+] macrophage subsets. These populations exhibit broad colony-stimulating factor 1 receptor (Csf1r) expression, accompanied by enhanced CSF signaling and macrophage-centered intercellular communication, implicating CSF1R-associated macrophage remodeling in post-ablation immunosuppression. Accordingly, an albumin-based lipoprotein nanosystem co-encapsulating paclitaxel (PTX) and the CSF1R inhibitor BLZ945 (PTX/BLZ945@Alb-lip) was developed. Across multiple tumor models, PTX/BLZ945@Alb-lip enhances immunomodulator delivery to both TDLNs and tumors, remodels the macrophage-mediated immunosuppressive microenvironment, and suppresses residual tumor growth after iMWA. Moreover, treatment promotes durable antitumor immune memory and protects cured mice against tumor rechallenge. These findings identify TDLNs as an important therapeutic site in post-ablation immunotherapy and provide a potential strategy to prevent tumor recurrence following ablation.

Late occurrence of breast cancer brain metastases in patients pretreated with systemic therapies is often associated with therapy resistant brain metastatic lesions. Prior studies targeting previously identified mediators of resistance have yielded limited success, especially in the case of brain metastatic breast cancer (BMBC). Trefoil Factor 1 (TFF1) has been associated with therapy resistance in Estrogen Receptor (ER) positive breast cancer. However, its role in therapy resistance of triple negative and HER2+ breast cancer remains elusive. Herein, we assessed the involvement of TFF1 in therapy resistant triple negative and HER2+ BMBC. We developed Paclitaxel resistant triple negative and Lapatinib resistant HER2+ BMBC cells by dose escalation method. Drug efflux transporter ABCB1 in Paclitaxel resistant cells and ABCG2 in Lapatinib resistant cells were significantly upregulated. Additionally, cancer stem cell marker, CD24, showed significant upregulation in both resistant cell lines while anti-apoptotic protein BCL2 was upregulated only in Lapatinib resistant cells. Importantly, TFF1 was significantly upregulated in both Paclitaxel and Lapatinib resistant BMBC cells. Moreover, siRNA mediated TFF1 silencing partially alleviated resistance in both Paclitaxel and Lapatinib resistant BMBC cells. Our study shows that TFF1 is potentially associated with resistance to Paclitaxel and Lapatinib in both triple negative and HER2+ BMBC.

Gastric cancer (GC) is a leading cause of cancer death globally. Platinum‑based drugs, fluoropyrimidines, and docetaxel are standard for advanced disease, but intrinsic and acquired resistance limit the efficacy. This review summarizes chemoresistance mechanisms, focusing on the roles of various cell death pathways in GC chemoresistance, as well as the involvement of non-coding RNAs (ncRNAs) in modulating drug resistance through multiple regulatory mechanisms. We also describe models for establishing resistant cell lines (stepwise dose escalation, high-dose intermittent pulse selection, gene transfection).