Recent advances in chimeric antigen receptor (CAR)-T cell therapy have revolutionized the therapeutic landscape for relapsed/refractory (R/R) hematological malignancies, especially for B-cell non-Hodgkin lymphoma (B-NHL). By modifying T cells, CAR-T cells can specifically recognize the antigens expressed on the surface of lymphoma cells, and exert the function of killing tumor cells. CD19-targeted CAR-T cell therapy has been demonstrated as an effective treatment for R/R diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) [1]. Four kinds of CD19 CAR-T products are currently FDA-approved for treating R/R B-cell lymphomas [2]. Additionally, CAR-T cells targeting against alternative antigens are in the midst of clinical trials. CD20-directed CAR-T cells have been observed to induce overall response rates (ORRs) of 81–86 % in R/R DLBCL [[3], [4], [5]], while bispecific CD19/CD20 CAR-T cells achieve an ORR of 90 % in R/R B-NHL [6,7]. For patients with R/R DLBCL developing resistance to CD19-targeted CAR-T cells, CAR-T cells targeting CD22 provide alternative treatment options [8], with an ORR of 85 % [9]. Dual-target of CD19/CD22 CAR-T cells achieved durable responses in R/R large B-cell lymphoma (LBCL), with complete response (CR) rates of 29 %–48.9 % [10,11]. Allogeneic CD7 CAR-T cells exhibit an ORR of 81.8 % in T-cell lymphoma/leukemia [12]. In Hodgkin lymphoma, combined CD30 CAR-T cell therapy with autologous hematopoietic stem cell transplantation (ASCT) yields a high response rates, with 1-year progression-free survival (PFS) rate of 36 % and 1-year overall survival (OS) rate of 94 % [13].

Although CAR-T cell therapy has achieved success in treating lymphoma, it still faces several major challenges. Lack of persistence and activity of CAR-T cells, tumor antigen loss, immune evasion, and immunosuppressive tumor microenvironment (TME) lead to disease progression or relapse via alternative pathways [14]. The complex TME, which is comprised of tumor cells, immune cells, cytokines, stromal cells (e.g., cancer-associated fibroblasts [CAFs], vascular endothelial cells), and extracellular matrix (ECM) [15], impacts CAR-T cell trafficking, persistence, and cytotoxicity in lymphoma, which shares characteristics like “solid tumors” [16,17]. The interactions between virous TME components play vital roles on resistance to treatment and tumor progression. Regulatory T cells (Tregs), which are differentiated from traditional T cells within the TME, play immunosuppressive roles, thus suppressing antitumor immunity, and promoting tumor growth [18]. Tumor-associated macrophages (TAMs), derived from immature myeloid precursors, possess dual roles of tumor promotion and tumor suppression. Transforming growth factor-β (TGF-β) promotes lymphoma progression by inhibiting antigen presentation, suppressing cytokine production, promoting Tregs differentiation and augmenting the immunosuppressive activity of dendritic cells (DCs) and so on [19]. Interferon-γ (IFN-γ) and interleukin (IL) −2 exert antitumor immunity by activating DCs and cytotoxic T lymphocytes (CTLs) [20]. In the hypoxic TME conditions, the expansion and activity of CAR-T cells are impaired [21]. The various components of TME interact and establish an immunosuppressive microenvironment that diminishes CAR-T cell efficacy. Here, we summarize the characteristics of TME in lymphoma, and the impact of TME on CAR-T cell therapy. We also discuss strategies to modulate TME components, target immunosuppressive cells, and overcome inhibitory signaling pathways to enhance the persistence and cytotoxicity of CAR-T cells.