Liposomal Nω-hydroxy-l-norarginine, a proof-of-concept: Arginase inhibitors can be incorporated in liposomes while retaining their therapeutic activity ex vivo.

Cancer immunotherapy has evolved significantly over the last decade, with therapeutics targeting the adaptive immune system showing exciting effects in clinics. Yet, the modulation of the innate immune system, particularly the tumor-associated innate immune cells which are an integral part of immune responses in cancer, remains less understood. The arginase 1 (Arg1) pathway is a pivotal metabolic pathway that tumor-associated innate immune cells exploit to create an immunosuppressive tumor microenvironment, leading to the evasion of immune surveillance.

Elucidating the power of arginine restriction: taming type I interferon response in breast cancer via selective autophagy.

Background: Type I interferons (IFN-I) are potent alarm factors that initiate cancer cell elimination within tumors by the immune system. This critical immune response is often suppressed in aggressive tumors, thereby facilitating cancer immune escape and unfavorable patient outcome. The mechanisms underpinning IFN-I suppression in tumors are incompletely understood.

Discovery of a new marker to identify myeloid cells associated with metastatic breast tumours.

Background: Myeloid cells play an essential role in cancer metastasis. The phenotypic diversity of these cells during cancer development has attracted great interest; however, their functional heterogeneity and plasticity have limited their role as prognostic markers and therapeutic targets.

Methods: To identify markers associated with myeloid cells in metastatic tumours, we compared transcriptomic data from immune cells sorted from metastatic and non-metastatic mammary tumours grown in BALB/cJ mice.

Synthesis and Development of Highly Selective Pyrrolo[2,3-]pyrimidine CSF1R Inhibitors Targeting the Autoinhibited Form.

Colony-stimulating factor-1 receptor (CSF1R) is a receptor tyrosine kinase that controls the differentiation and maintenance of most tissue-resident macrophages, and the inhibition of CSF1R has been suggested as a possible therapy for a range of human disorders. Herein, we present the synthesis, development, and structure-activity relationship of a series of highly selective pyrrolo[2,3-]pyrimidines, showing subnanomolar enzymatic inhibition of this receptor and with excellent selectivity toward other kinases in the platelet-derived growth factor receptor (PDGFR) family. The crystal structure of the protein and revealed that the binding conformation of the protein is DFG-out-like.

A highly selective purine-based inhibitor of CSF1R potently inhibits osteoclast differentiation.

The colony-stimulating factor 1 receptor (CSF1R) plays an important role in the regulation of many inflammatory processes, and overexpression of the kinase is implicated in several disease states. Identifying selective, small-molecule inhibitors of CSF1R may be a crucial step toward treating these disorders. Through modelling, synthesis, and a systematic structure-activity relationship study, we have identified a number of potent and highly selective purine-based inhibitors of CSF1R.

NRF2 drives an oxidative stress response predictive of breast cancer.

Many breast cancer patients are diagnosed with small, well-differentiated, hormone receptor-positive tumors. Risk of relapse is not easily identified in these patients, resulting in overtreatment. To identify metastasis-related gene expression patterns, we compared the transcriptomes of the non-metastatic 67NR and metastatic 66cl4 cell lines from the murine 4T1 mammary tumor model.

Tumor Targeting by αβ-Integrin-Specific Lipid Nanoparticles Occurs Phagocyte Hitchhiking.

Although the first nanomedicine was clinically approved more than two decades ago, nanoparticles' (NP) behavior is complex and the immune system's role in their application remains elusive. At present, only passive-targeting nanoformulations have been clinically approved, while more complicated active-targeting strategies typically fail to advance from the early clinical phase stage. This absence of clinical translation is, among others, due to the very limited understanding for targeting mechanisms.

GREM1 is associated with metastasis and predicts poor prognosis in ER-negative breast cancer patients.

Background: In breast cancer, activation of bone morphogenetic protein (BMP) signaling and elevated levels of BMP-antagonists have been linked to tumor progression and metastasis. However, the simultaneous upregulation of BMPs and their antagonist, and the fact that both promote tumor aggressiveness seems contradictory and is not fully understood.

Methods: We analyzed the transcriptomes of the metastatic 66cl4 and the non-metastatic 67NR cell lines of the 4T1 mouse mammary tumor model to search for factors that promote metastasis.