Different stimuli can polarize macrophages into two basic types, M1 and M2. Tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) are composed of heterogeneous subpopulations, which include the M1 anti-tumor and M2 pro-tumor phenotypes. TAMs predominantly play a M2-like tumor-promoting role in the TME and regulate various malignant effects, such as angiogenesis, immune suppression, and tumor metastasis; hence, TAMs have emerged as a hot topic of research in cancer therapy. This review focuses on three main aspects of TAMs. First, we summarize macrophage polarization along with the effects on the TME. Second, recent advances and challenges in cancer treatment and the role of M2-like TAMs in immune checkpoint blockade and CAR-T cell therapy are emphasized. Finally, factors, such as signaling pathways, associated with TAM polarization and potential strategies for targeting TAM repolarization to the M1 pro-inflammatory phenotype for cancer therapy are discussed.

Acute myeloid leukemia (AML) is one of the most common types of adult acute leukemia. Standard chemotherapies can induce complete remission in selected patients; however, a majority of patients eventually relapse and succumb to the disease. Thus, the development of novel therapeutics for AML is urgently needed. Human C-type lectin-like molecule-1 (CLL-1) is a type II transmembrane glycoprotein, and its expression is restricted to myeloid cells and the majority of AML blasts. Moreover, CLL-1 is expressed in leukemia stem cells (LSCs), but absent in hematopoietic stem cells (HSCs), which may provide a potential therapeutic target for AML treatment. We tested the expression of CLL-1 antigen on peripheral blood cells and bone marrow cells in healthy donor and AML patients. Then, we developed a chimeric antigen receptor (CAR) containing a CLL1-specific single-chain variable fragment, in combination with CD28, 4-1BB costimulatory domains, and CD3-ζ signaling domain. We further investigate the function of CLL-1 CAR-T cells. The CLL-1 CAR-T cells specifically lysed CLL-1+ cell lines as well as primary AML patient samples in vitro. Strong anti-leukemic activity was observed in vivo by using a xenograft model of disseminated AML. Importantly, CLL-1+ myeloid progenitor cells and mature myeloid cells were specifically eliminated by CLL-1 CAR-T cells, while normal HSCs were not targeted due to the lack of CLL-1 expression. CLL-1 CAR-T represents a promising immunotherapy for the treatment of AML.

As a widely recognized standard regimen, R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is able to cure two-thirds patients with diffuse large B cell lymphoma (DLBCL), and the remaining patients suffer from refractory or relapsed disease due to resistance to R-CHOP and fare poorly. Unsatisfied outcomes for those relapsed/refractory patients prompted efforts to discover new treatment approaches for DLBCL, including chimeric antigen receptor T cells, bispecific T cell engagers, immunomodulatory drugs, immune checkpoint inhibitors, monoclonal antibodies, antibody–drug conjugates, molecular pathway inhibitors, and epigenetic-modifying drugs. Herein, up-to-date data about the most promising treatment approaches for DLBCL are recapitulated, and novel genetic classification systems are introduced to guide individualized treatment for DLBCL.

Chimeric Antigen Receptor (CAR)-T-cell therapy has revolutionized cancer immune therapy. However, challenges remain including increasing efficacy, reducing adverse events and increasing accessibility. Use of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) technology can effectively perform various functions such as precise integration, multi-gene editing, and genome-wide functional regulation. Additionally, CRISPR screening using large-scale guide RNA (gRNA) genetic perturbation provides an unbiased approach to understanding mechanisms underlying anti-cancer efficacy of CAR T-cells. Several emerging CRISPR tools with high specificity, controllability and efficiency are useful to modify CAR T-cells and identify new targets. In this review we summarize potential uses of the CRISPR system to improve results of CAR T-cells therapy including optimizing efficacy and safety and, developing universal CAR T-cells. We discuss challenges facing CRISPR gene editing and propose solutions highlighting future research directions in CAR T-cell therapy.

Although the first-line rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone regimen (R-CHOP) substantially improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL), 40% of the patients suffered from relapsed/refractory disease and had poor survival outcomes. The detailed mechanism underlying R-CHOP resistance has not been well defined. For this review, we conducted a thorough search for literature and clinical trials involving DLBCL resistance. We discussed DLBCL biology, epigenetics, and aberrant signaling of the B-cell receptor (BCR), phosphatidylinositol 3-kinase (PI3K)/Akt, nuclear factor kappa light chain enhancer of activated B-cells (NF-κB), and the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) pathways as defining mechanisms of DLBCL heterogeneity and R-CHOP resistance. The cell of origin, double- or triple-hit lymphoma and double-protein-expression, clonal evolution, tumor microenvironment, and multi-drug resistance help to contextualize DLBCL resistance in an (epi)genetically and biologically comparative manner. With better understanding of the biological and molecular landscape of DLBCL, a more detailed classification system and tailored treatments will ideally become available to further improve the prognosis of DLBCL patients.

Chimeric antigen receptor (CAR)-T-cell therapies have exhibited remarkable efficacy in the treatment of hematologic malignancies, with 9 CAR-T-cell products currently available. Furthermore, CAR-T cells have shown promising potential for expanding their therapeutic applications to diverse areas, including solid tumors, myocardial fibrosis, and autoimmune and infectious diseases. Despite these advancements, significant challenges pertaining to treatment-related toxic reactions and relapses persist. Consequently, current research efforts are focused on addressing these issues to enhance the safety and efficacy of CAR-T cells and reduce the relapse rate. This article provides a comprehensive overview of the present state of CAR-T-cell therapies, including their achievements, existing challenges, and potential future developments.