Microbe-based cancer immunotherapy has recently emerged as a hot topic for cancer treatment. However, serious limitations remain including infection associated side-effect and unsatisfactory outcomes in clinic trials. Here, we fabricate different sizes of nano-formulations derived from yeast cell wall (YCW NPs) by differential centrifugation. The induction of anticancer immunity of our formulations appears to inversely correlate with their size due to the ability to accumulate in tumor-draining lymph node (TDLN). Moreover, we use a percolation model to explain their distribution behavior toward TDLN. The abundance and functional orientation of each effector component are significantly improved not only in the microenvironment in tumor but also in the TDLN following small size YCW NPs treatment. In combination with programmed death-ligand 1 (PD-L1) blockade, we demonstrate anticancer efficiency in melanoma-challenged mice. We delineate potential strategy to target immunosuppressive microenvironment by microbe-based nanoparticles and highlight the role of size effect in microbe-based immune therapeutics.

SMAD4 is the only common SMAD in TGF-β signaling that usually impedes immune cell activation in the tumor microenvironment. However, we demonstrated here that selective deletion of Smad4 in NK cells actually led to dramatically reduced tumor cell rejection and augmented tumor cell metastases, reduced murine CMV clearance, as well as impeded NK cell homeostasis and maturation. This was associated with a downregulation of granzyme B (Gzmb), Kit, and Prdm1 in Smad4-deficient NK cells. We further unveiled the mechanism by which SMAD4 promotes Gzmb expression. Gzmb was identified as a direct target of a transcriptional complex formed by SMAD4 and JUNB. A JUNB binding site distinct from that for SMAD4 in the proximal Gzmb promoter was required for transcriptional activation by the SMAD4-JUNB complex. In a Tgfbr2 and Smad4 NK cell–specific double–conditional KO model, SMAD4-mediated events were found to be independent of canonical TGF-β signaling. Our study identifies and mechanistically characterizes unusual functions and pathways for SMAD4 in governing innate immune responses to cancer and viral infection, as well as NK cell development.

While hypoxia promotes carcinogenesis, tumour aggressiveness, metastasis, and resistance to oncological treatments, the impacts of hyperoxia on tumours are rarely explored because providing a long-lasting oxygen supply in vivo is a major challenge. Herein, we construct micro oxygen factories, namely, photosynthesis microcapsules (PMCs), by encapsulation of acquired cyanobacteria and upconversion nanoparticles in alginate microcapsules. This system enables a long-lasting oxygen supply through the conversion of external radiation into red-wavelength emissions for photosynthesis in cyanobacteria. PMC treatment suppresses the NF-kB pathway, HIF-1α production and cancer cell proliferation. Hyperoxic microenvironment created by an in vivo PMC implant inhibits hepatocarcinoma growth and metastasis and has synergistic effects together with anti-PD-1 in breast cancer. The engineering oxygen factories offer potential for tumour biology studies in hyperoxic microenvironments and inspire the exploration of oncological treatments.

BCMA-targeting chimeric antigen receptor (CAR) T cell therapy demonstrates impressive clinical response in multiple myeloma (MM). However, some patients with BCMA-deficient tumours cannot benefit from this therapy, and others can experience BCMA antigen loss leading to relapse, thus necessitating the identification of additional CAR-T targets. Here, we show that FcRH5 is expressed on multiple myeloma cells and can be targeted with CAR-T cells. FcRH5 CAR-T cells elicited antigen-specific activation, cytokine secretion and cytotoxicity against MM cells. Moreover, FcRH5 CAR-T cells exhibited robust tumoricidal efficacy in murine xenograft models, including one deficient in BCMA expression. We also show that different forms of soluble FcRH5 can interfere with the efficacy of FcRH5 CAR-T cells. Lastly, FcRH5/BCMA-bispecific CAR-T cells efficiently recognized MM cells expressing FcRH5 and/or BCMA and displayed improved efficacy, compared with mono-specific CAR-T cells in vivo. These findings suggest that targeting FcRH5 with CAR-T cells may represent a promising therapeutic avenue for MM.

Advances in the development of therapeutic extracellular vesicles (EVs) for cancer immunotherapy have allowed them to emerge as an alternative to cell therapy. In this proof-of-concept work, we develop bispecific EVs (BsEVs) by genetically engineering EV-producing dendritic cells (DCs) with aCD19 scFv and PD1 for targeting tumor antigens and blocking immune checkpoint proteins simultaneously. We find that these bispecific EVs (EVs-PD1-aCD19) have an impressive ability to accumulate in huCD19-expressing solid tumors following intravenous injection. In addition, EVs-PD1-aCD19 can remarkably reverse the immune landscape of the solid tumor by blocking PD-L1. Furthermore, EVs-PD1-aCD19 can also target tumor-derived EVs in circulation, which prevents the formation of a premetastatic niche in other tissues. Our technology is a demonstration of bispecific EV-based cancer immunotherapy, which may inspire treatments against various types of tumors with different surface antigens and even a patient-tailored therapy.