Highlights d A distinct B cell subset emerges in tumors after chemotherapy d B cells elicit anti-tumor T cell immunity by ICOSL d Complement signals initiated by immunogenic cell death shape B cell phenotypes d Tumor CD55 expression determines the opposite effects of B cells in tumors

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Carcinoma-associated fibroblasts (CAFs) consist of heterogeneous subpopulations that play a critical role in the dynamics of the tumor microenvironment. The extracellular signals of CAFs have been attributed to the extracellular matrix, cytokines, cell surface checkpoints, and exosomes. In the present study, it is demonstrated that the CD10 transmembrane hydrolase expressed on a subset of CAFs supports tumor stemness and induces chemoresistance. Mechanistically, CD10 degenerates an antitumoral peptide termed osteogenic growth peptide (OGP). OGP restrains the expression of rate-limiting desaturase SCD1 and inhibits lipid desaturation, which is required for cancer stem cells (CSCs). Targeting CD10 significantly improves the efficacy of chemotherapy in vivo. Clinically, CD10-OGP signals are associated with the response to neoadjuvant chemotherapy in patients with breast cancer. The collective data suggest that a nexus between the niche and lipid metabolism in CSCs is a promising therapeutic target for breast cancer.

Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long‐term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell‐intrinsic CD96 enhances the chemotherapeutic response in a patient‐derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β‐oxidation via the CD155‐CD96‐Src‐Stat3‐Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell‐intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

Immunotherapy Immunotherapy using immune checkpoint inhibitors has revolutionized anticancer treatment. In article number 2202956, Qiyi Zhao and co‐workers discover CD96, a novel immune checkpoint protein, expressed in cancer cell exhibit features indicative of both breast cancer stem cells (BCSCs) and chemoresistance. The cover, in the Chinese traditional allusions to idioms, represents “killing two birds with one stone”, in which arrow signifies CD96 blocking antibody and eagles signify immune cells and BCSCs, respectively. The image represents CD96 blocking not only increases anti‐tumor immunity but also promotes tumor cell killing by chemotherapeutic drugs.