Although KRAS mutations are one of the most common recurrent alterations, treatments are lacking for the majority of KRAS mutant tumors. Mutant KRAS can promote evasion of the adaptative immune response; however, its influence on the innate response is unclear. Hu and colleagues, utilizing both in vitro and in vivo non-small cell lung cancer models and patient samples, demonstrated that mutant KRAS drives innate immunoevasion through upregulation of cluster of differentiation 47 (CD47), which acts as a “don't eat me” signal. CD47 prevented macrophage-dependent phagocytosis and promoted tumorigenesis. Conversely, mutant KRAS inhibition decreased CD47 expression and restored phagocytosis and innate immunity.

Expert Commentary: This study suggests that targeting CD47 in KRAS mutant non-small cell lung cancer may be an effective therapeutic strategy.

Hu H, Cheng R, Wang Y, Wang X, Wu J, Kong Y, et al. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47. J Clin Invest 2023;17;133:e153470. doi: 10.1172/JCI153470.


In glioblastoma (GBM), the most frequent and incurable brain tumor, TP53, is wildtype, however, there must be some mechanism by which tumors resist p53-driven growth inhibition. Sun and colleagues showed that the chromatin regulator bromodomain-containing protein 8 (BRD8) promotes binding of the histone variant H2AZ at p53 targets, preventing p53 from occupying binding sites in GBM cells. This epigenetic change to a closed chromatin state inhibits cell-cycle progression. Upon targeting BRD8, H2AZ was removed and p53 function restored with inhibition of cell proliferation. Using single-cell sequencing, the authors showed that proliferating cancer cells expressed both BRD8 and H2AZ, with low levels of the p53 target gene encoding the cell-cycle target protein p21.

Expert Commentary: This work demonstrates that BRD8 is a promising target for GBM.

Sun X, Klingbeil O, Lu B, Wu C, Ballon C, Ouyang M, et al. BRD8 maintains glioblastoma by epigenetic reprogramming of the p53 network. Nature 2023;613:195-202.


While anti-PD-1–based checkpoint blockade clearly acts on CD8+ T cells, it's impact on regulatory T cells (Tregs) is less clear. Using tamoxifen-regulated Cre recombinase to delete PD-1 specifically in Tregs just prior to tumor inoculation, Kim and colleagues showed that mice with PD-1–deficient Tregs better controlled the growth of multiple tumors. Interestingly, PD-1 deletion shortly after tumor inoculation did not control tumor growth, indicating an early requirement for PD-1 activity in Treg-control of tumors. Similarly, anti-PD-1 antibody therapy in pre-formed tumors acted principally on CD8+ T cells. However, anti-PD-1 antibodies still altered the phenotype of Tregs. Mechanistically, PD-1 supported Treg-favored fatty acid oxidation and maintained Foxp3 expression.

Expert Commentary: PD-1 activity in tumor-infiltrating Tregs supports their suppressive activity, revealing an additional therapeutic target underlying the effectiveness of anti-PD-1 checkpoint blockade.

Kim MJ, Kim K, Park HJ, Kim GR, Hong KH, Oh JH, et al. Deletion of PD-1 destabilizes the lineage identity and metabolic fitness of tumor-infiltrating regulatory T cells. Nat Immunol 2023;24:148-61.


Inactivated tumor cells have previously been used for cancer therapy to act as a source of neoantigens to illicit immune responses, but the results have been underwhelming. To create a durable anticancer adaptive immune response, Chen and colleagues administered a vaccine with genetically modified live cancer cells including “kill switches” for inducible elimination. Using the syngeneic CT2A model of glioblastoma, the authors engineered tumor cells to express potent immunostimulatory cytokines GM-CSF and IFNβ, as well as removing their ability to initiate autotoxic interferon signaling. Engraftment with these cells, unlike other CT2A variants, did not result in tumors. Similar results were seen in related models of recurrence and metastasis.

Expert Commentary: While engineering of CT2A and mouse lung carcinoma cells was effective in tumor clearance, this effect was less pronounced in an engrafted humanized mouse model. It will be critical to see how engineered cells perform in early clinical trials or in additional models where modified cells are not part of the initial graft.

Chen KS, Reinshagen C, Schaik TA, Rossignoli F, Borges P, Mendonca NC, et al. Bifunctional cancer cell-based vaccine concomitantly drives direct tumor killing and antitumor immunity. Sci Transl Med 2023;15:eabo4778. doi: 10.1126/scitranslmed.abo4778.


Abundant stroma and severe fibrosis are hallmarks of intractable pancreatic and diffuse-type gastric cancers (DGC). Akiyama and colleagues studied underlying mechanisms of PDGF–PDGFR-mediated fibrosis and consequences of PDGF–PDGFR inhibition on the immune microenvironment. Expression of PDGF C and D correlated with poor prognosis in DGC patients, and expression of PDGFRβ was high in DGC stroma. Stimulation with PDGF increased growth of cancer-associated fibroblasts and expression of CXCLs, which were blocked by dual PDGFRα/β inhibitors. In a fibrotic tumor model with an immunosuppressive microenvironment, dual PDGFRα/β blockade with regorafenib reversed the immunosuppressive microenvironment through stromal modification and synergized with anti-PD-1 immunotherapy.

Expert Commentary: Dual inhibition of PDGFRα/β and immune checkpoints provides a promising therapeutic strategy in fibrotic cancers.

Akiyama T, Yasuda T, Uchihara T, Yasuda-Yoshihara N, Tan BJHY, Yonemura A, et al. Stromal reprogramming through dual PDGFRα/β blockade boosts the efficacy of anti-PD-1 immunotherapy in fibrotic tumors. Cancer Research; Published OnlineFirst December 21, 2022; doi: 10.1158/0008-5472.CAN-22-1890.


Hypomethylating agents (HMA) are used to reprogram tumor cells during the treatment of myelodysplastic neoplasms and chronic myelomonocytic leukemia, diseases that arise from accumulation of somatic mutations in hematopoietic stem cells. Schnegg-Kaufmann and colleagues asked whether mutational burden of the mutant clones influences productive hematopoiesis and response to HMA therapy. Stem, progenitor, and differentiated cells all showed similar mutational loads. Attrition of highly mutated cells was not observed, suggesting that highly mutated stem and progenitor cells retained capacity to differentiate. HMA therapy therefore enables increased productive hematopoiesis from mutant clones.

Expert Commentary: This work questions therapeutic principles where clinical improvements are thought to be reliant on ablation of the mutant clones.

Schnegg-Kaufmann AS, Thoms JAI, Bhuyan GS, Hampton H, Vaughan L, Rutherford KD, et al. Contribution of mutant HSC clones to immature and mature cells in MDS and CMML, and variations with AZA therapy. Blood; Published online December 9, 2022; doi: 10.1182/blood.2022018602.

Note: Breaking Insights are written by Cancer Research editors. Readers are encouraged to consult the articles referred to in each item for full details on the findings described.