**4. Perspectives and future directions**

For decades, comprehensive strategies for eliciting anticancer immunity have been extensively explored [34]. In particular, antitumor immunotherapies involving adoptive cellular transfer or immune checkpoint inhibitors are validated as effective and promising treatment option for hematopoietic malignancies and solid tumors [78]. Of the obstacles, tumor escape and cytotoxicity are the core burning issues in oncotherapy. To overcome the shortcomings, the systematic and precise understanding of TMEs and the relevant networks including pro- and anti-inflammatory cytokines, immunosuppressive cells, tumor-associated stroma, tumor hypoxia and metabolism as well as immune inhibitory checkpoints are collectively of great importance for improving the trafficking and delivery efficacy of CAR-transduced immune cells into the tumor site and helping solve the drawback of tumor antigen heterogeneity [108].

State-of-the-art updates have indicated the rosy and powerful implement of the anti-cancer immunotherapy including adoptive cellular transplantation and immunecheckpoint inhibitors for solid tumor and hematologic malignancy management in both preclinical studies and clinical practices [142, 143]. Nevertheless, the potentially acute and chronic adverse effects caused by immunotherapy-associated cytotoxicity have led to severe outcomes in tumor patients such as neurotoxicity, aGvHD, innate or acquired resistance, autoimmunity, nonspecific inflammation, cytokine storm syndrome (CSS), and the difficulty in realizing controllable modulation of the immune response, which are also the prerequisites and key challenges in the extensive implementation of immunotherapy for tumor, and in particular, the hurdles in adoptive T cell-based immunotherapy and double-edged properties of cancer immunoediting [75, 142, 143].

As to gene-edited adoptive immune cells, improvement strategies for enhancing the transfection efficiency and target selection as well as efficiently reducing the concomitant cytotoxicity during cancer immunotherapy are the key issue. For example, even though CAR-NKs exhibit inferior baseline cytotoxicity and preferable tumor killing activity when compared with other sources, yet the occasional issues should be systematically and thoroughly overcome by subsequent stimulation with optimized cytokine cock-tails [27, 144]. Therefore, it is of great importance to explore emerging features for the efficient development of novel immunotherapies, such as the selection of ideal CARs or TCRs targeting validated antigenic epitopes with well-characterized tumor cell expression and processing, enhancing immune cell effector function, persistence, expansion, trafficking, and memory formation by strategic selection of co-stimulated substrate cells, and novel technologies for gene-engineering [21, 27].

Of note, the variations and adverse effects in cancer immunotherapy reveals the heterogeneity and instability of the current immune cell products, and thus highlight the necessity and urgency of industrialization and standardization for clinical applications [145]. Generally, a cohort of core issues both in fundamental research and clinical practice of cancer immunotherapy need to be improved before large-scale applications [21, 146]. For instance, the screening criteria of healthy tissues for generating immune cell sources, the standardized regents and procedures for cell product preparation, the dose and frequency of cell transplantation, the delivery strategies and targets for engineered cells [147–149]. Therefore, it is of great importance for the generation of clinical-grade immune cell products based on good manufacturing practice (GMP) and convenient to universally improve life quality of patients with standard supervision. Additionally, multidisciplinary research has also highlighted the feasibility and prospective of nanomaterials (e.g., surface-conjugated nanoparticles, injectable scaffolds) as promising agents for cancer therapy attribute to the rapid progresses of nanobiotechnology and clinical biomedicine [18–20].

Collectively, comprehensive treatment strategies by combining the conventional remedies (eg., laparoscopic rectal surgery, robotic surgery, radiotherapy, chemotherapy, drugs), checkpoint blockade (e.g., PD-1/PD-L1, CTLA-4), vaccines (e.g., mRNAs), biomaterials (e.g., nanoparticles) with the aforementioned cellular immunotherapy will largely benefit the malignancy management and effectively reduce the cytotoxicity [21, 108, 150–152].
