T cell rejuvenation by PD-1/PD-L1 blockade, despite emerging as a highly promising therapy for advanced cancers, is only beneficial for a minority of treated patients. There is evidence that a lack of efficient T cell activation may be responsible for the failure. Here, we demonstrate that IL-21 can be targeted to tumor-reactive T cells by fusion of IL-21 to anti-PD-1 antibody. To our surprise, the fusion protein PD-1Ab21 promotes the generation of memory stem T cells (TSCM) with enhanced cell proliferation. PD-1Ab21 treatment show potent antitumor effects in established tumor-bearing mice accompanied with an increased frequency of TSCM and robust expansion of tumor-specific CD8+ T cells with a memory phenotype, and is superior to a combination of PD-1 blockade and IL-21 infusion. Therefore, we have developed a potential strategy to improve the therapeutic effects of immune checkpoint blockade by simultaneously targeting cytokines to tumor-reactive T cells.

Identification of effective therapies for colorectal cancer (CRC) remains an urgent medical need, especially for the microsatellite-stable (MSS) phenotype. In the current study, a combination of fruquintinib plus anti–PD-1 for MSS CRC therapy was investigated. First, a case of advanced MSS CRC was reported. After failure of multiline therapy, the patient finally achieved rapid response after receiving fruquintinib plus anti–PD-1 treatment. Then the effect of fruquintinib plus anti–PD-1 was verified using a murine syngeneic model of CT26 cells (MSS). The results showed that cotreatment significantly inhibited tumor growth and promote survival time for tumor-bearing mice compared with the single drug alone. In addition, fruquintinib/anti–PD-1 cotreatment decreased angiogenesis, enhanced normalization of the vascular structure, and alleviated tumor hypoxia. Moreover, the combination therapy reprogrammed the immune microenvironment by enhancing chemotactic factor release, increasing CD8+ T cell infiltration and activation, decreasing ration of regulatory T cells, and promoting M1/M2 ratio of macrophage. Finally, the enhanced antitumor effect of fruquintinib/anti–PD-1 cotreatment was significantly reversed in CD8 knockout mice compared with that in the wild-type mice. Our study indicated that combination of fruquintinib and anti–PD-1 could synergistically suppress CRC progression and altered the tumor microenvironment in favor of antitumor immune responses.

Lead-free halide double perovskites (HDPs) have sparked broad interest in developing “green” photodetectors; however, self-powered X-ray detectors in this family remain elusive. Here, by exploiting the chirality-induced polar photovoltaic effect in a chiral-polar 2D HDP, (R-MPA)4AgBiI8 (1, R-MPA = R-β-methylphenethylammonium), we successfully realized self-powered X-ray detection. The significant spontaneous electric polarization in 1 gives it a large polar photovoltage of 0.36 V, which drives the separation and transport of X-ray-generated carriers, thus acquiring the capability of self-powered detection. Consequently, X-ray detectors based on high-quality single crystals of 1 exhibit a high sensitivity of 46.3 μC Gy–1 cm–2 and an ultralow detection limit of 85 nGy s–1 at zero bias. The sensitivity can be further increased to 949.6 μC Gy–1 cm–2 at 50 V bias, outperforming all current 2D HDP detectors. Our work is the first to demonstrate self-powered X-ray detection in single-phase lead-free HDPs, enlightening future design of “green” self-powered radiation detectors.