Colorectal cancer accounts for approximately 10 % of all newly diagnosed cancers and cancer-related deaths worldwide each year. It is the second most commonly diagnosed cancer in women and the third most common in men [1], [2]. In China, the prevalence of colorectal cancer has ranked second since 1990 and continues to rise steadily [3]. Surgery and chemotherapy remain the primary treatment options for most colorectal cancer patients. However, the prognosis remains poor due to limited therapeutic efficacy and intolerable toxicity.

In eukaryotic cells, DNA is wrapped around histone protein octamers, forming nucleosomes and chromatin. To regulate specific gene expression, chromatin-remodeling complexes, in coordination with transcription factors, create an intricate regulatory mechanism. Among these complexes, the mating-type switching (SWI)/sucrose fermentation (SNF) complex serves as a key regulator of nucleosome positioning [4].

The SWI/SNF complex was first identified in yeast and consists of more than 15 subunits. It plays a crucial role in activating gene expression, primarily through its ability to remodel and evict nucleosomes at gene promoters [5].

SMARCB1 was the first SWI/SNF subunit discovered to be mutated in cancer, such as malignant rhabdoid tumors [6], [7]. Additionally, the SS18–SSX fusion found in synovial sarcoma, which results in gain-of-function chromatin phenotypes, further highlights the association between SWI/SNF aberrations and cancer [8], [9].

In one of our previous CRISPR screenings, we identified SMARCD1 as one of the top candidates in PD-L1-low cells [10]. SMARCD1, along with SMARCC1, SMARCC2, and either of the ATPases SMARCA4 or SMARCA2, constitutes the core subunits of the three major subfamilies of mammalian SWI/SNF complexes: canonical BAF (cBAF), polybromo-associated BAF (pBAF), and non-canonical BAF (ncBAF) [11], [12]. SMARCD1 functions as a bridge between transcription factors and the SWI/SNF complex, thereby influencing the selective gene regulation mediated by SWI/SNF [13], [14]. The role of SMARCD1 varies across different tumor types. It has been reported that SMARCD1 suppresses the malignant phenotypes of human glioblastoma cells through crosstalk with the Notch signaling pathway [15], while promoting liver cancer growth via the mTOR pathway [16]. However, its role in colorectal cancer remains largely unexplored.

PD-L1 is one of the most well-known immune checkpoints. It is typically expressed in tumor cells and interacts with programmed cell death protein 1 (PD-1), which is predominantly expressed in immune cells. This interaction leads to immune cell exhaustion and apoptosis, ultimately weakening the immune response [17] Both PD-1 and PD-L1 have demonstrated significant therapeutic efficacy in solid tumor treatment, making the identification of novel immunotherapy targets highly promising.

Given the crucial role of SWI/SNF in cancer and the intriguing phenotype of SMARCD1 observed in our CRISPR/Cas9 screening for PD-L1 regulators, we investigated the function of SMARCD1 in this study. Our findings reveal that SMARCD1 deficiency leads to downregulation of PD-L1 expression and inhibits cancer cell proliferation (Fig. 1). These results identify SMARCD1 as a promising therapeutic target for anti-tumor therapy.